the asymmetric synthesis and reactions of...modern synthetic chemist’s armoury. new methods for...

The Asymmetric Synthesis and Reactions of

α-Functionalised Organometallic Reagents

Peter J. Rayner

PhD

University of York

Chemistry

July 2013

Abstract

i

Abstract

This thesis describes the development of new methods for the asymmetric synthesis of

α-alkoxy and α-amino organometallic reagents. Two approaches were taken: (i)

sulfoxide → magnesium exchange; (ii) asymmetric lithiation-trapping using chiral

bases. A review of this area is provided in Chapter One.

Chapter Two details the synthesis of α-alkoxy sulfoxides A in 99:1 er by asymmetric

lithiation using s-BuLi and chiral diamines and trapping with Andersen’s sulfinate. In

addition, an investigation into the lack of stereospecificity at sulfur during the trapping

process is presented. Finally, a sulfoxide → magnesium exchange was used to convert

the α-alkoxy sulfoxides into α-alkoxy Grignard reagents B and subsequent trapping

allows access to a range of products as single enantiomers. The remarkable

configurational stability of α-alkoxy Grignard reagents when compared to their

organolithium counterparts is of particular note.

SPh

O

CbO H

Ph

CbO H

MgCli-PrMgCl

THF, rt1 min B, 99:1 erA

Cb = CONiPr2

Attempts to use a similar method to synthesise α-amino sulfoxides in 99:1 er is

described in Chapter Three. Furthermore, insights are given into the surprising

instability of unsubstituted α-amino sulfoxides. Novel α-amino sulfoxides C were

designed to prohibit sulfoxide elimination. From the isolatable α-amino sulfoxides, the

synthesis and reactions of α-amino Grignard reagents D in 99:1 er via sulfoxide →

magnesium exchange is reported.

S

O

NBoc

NBoc

MgCl

i-PrMgCl

THF, rt1 min

D, 99:1 erC

In Chapter Four, an investigation into the mechanism of the asymmetric lithiation-

trapping of N-thiopivaloyl azetidine E using s-BuLi and chiral diamines is presented.

The configurational stability of the organolithium intermediate F was determined at −78

°C and the scope of electrophilic trapping was investigated.

N

S

N

S

Li

Et2O, _78 °C

s-BuLi, Chiral Diamine E+

N

S

E

E F

Table of Contents

ii

Table of Contents

Abstract .......................................................................................................................... i

Table of Contents ....................................................................................................... ii

List of Tables ............................................................................................................... v

Acknowledgements .................................................................................................. vii

Author’s Declaration ............................................................................................. viii

Chapter One: Introduction..................................................................................... 1

1.1 Asymmetric Synthesis of α-Functionalised Organolithium Reagents .............. 2

1.1.1 Enantioselective Deprotonation as a Route to Organolithium Reagents ......... 3

1.1.2 Dynamic Kinetic Resolution of Organolithium Reagents ............................. 15

1.1.3 Dynamic Thermodynamic Resolution of Organolithium Reagents ............... 19

1.2 Asymmetric Synthesis of α-Functionalised Organomagnesium Reagents ..... 25

1.2.1 Asymmetric Synthesis of Grignard Reagents by Lithium → Magnesium

Transmetallation ...................................................................................................... 26

1.2.2 Asymmetric Synthesis of Grignard Reagents by Sulfoxide → Magnesium

Exchange ................................................................................................................. 27

1.3 Project Outline .................................................................................................... 33

Chapter Two: Synthesis and Reactions of α-Alkoxy Grignard Reagents

......................................................................................................................................... 37

2.1 Previous Syntheses of α-Alkoxy Sulfoxides ...................................................... 38

2.2 Synthesis of α-Alkoxy Sulfoxides ....................................................................... 42

2.2.1 s-BuLi/TMEDA-Mediated Lithiation of O-Alkyl Carbamates and Trapping

with Andersen’s Sulfinate ....................................................................................... 42

2.2.2 s-BuLi/Chiral Ligand-mediated Lithiation of O-Alkyl Carbamates and

Trapping with Andersen’s Sulfinate ....................................................................... 50

Table of Contents

iii

2.3 Sulfoxide → Magnesium Exchange of α-Alkoxy Sulfoxides ........................... 55

2.3.1 Optimising the Sulfoxide → Magnesium Exchange Reaction ...................... 55

2.3.2 Synthesis and Reactions of Enantiopure α-Alkoxy Grignard Reagents ........ 58

2.4 Synthesis of Tertiary Alcohols from Sulfoxides via Sulfoxide → Magnesium

Exchange .................................................................................................................... 63

2.5 Conclusions and Future Work ........................................................................... 68

Chapter Three: Synthesis and Reactions of α-Amino Grignard

Reagents ....................................................................................................................... 70

3.1 Previous Syntheses of α-Amino Sulfoxides, Sulfides and Sulfones ................. 71

3.2 Attempted synthesis of Pyrrolidinyl and Piperidinyl α-Amino Sulfoxides .... 74

3.2.1 Attempted Synthesis of Pyrrolidinyl and Piperidinyl α-Amino Sulfoxides via

Lithiation-Trapping ................................................................................................. 74

3.2.2 Attempted synthesis of Pyrrolidinyl and Piperidinyl α-Amino Sulfoxides via

Oxidation of Sulfides .............................................................................................. 80

3.3 Attempted Synthesis of Cyclic and Acyclic α-Amino Sulfoxides .................... 83

3.3.1 Attempted Synthesis of Cyclic N-Amido and N-Thioamide Sulfoxides ....... 83

3.3.2 Synthesis of Acyclic α-Amino Sulfoxides ..................................................... 88

3.4 Synthesis of Azabicyclo[3.1.0]hexane Sulfoxides ............................................. 95

3.4.1 Lithiation-Trapping of N-Boc 4-Chloro and 4-Sulfonyl Piperidines ............. 96

3.4.2 s-BuLi/TMEDA-Mediated Lithiation of N-Boc 4-Chloro Piperidine and

Trapping with Andersen’s Sulfinate ....................................................................... 98

3.4.3 s-BuLi/Chiral Diamine-Mediated Lithiation of N-Boc 4-Chloro Piperidine

and Trapping with Andersen’s Sulfinate .............................................................. 102

3.5 Sulfoxide → Magnesium Exchange ................................................................. 117

3.5.1 Sulfoxide → Magnesium Exchange Reactions ............................................ 117

3.5.2 Proof of Stereochemistry and Formal Synthesis of Saxagliptin .................. 118

3.6 Conclusions and Future Work ......................................................................... 124

Table of Contents

iv

Chapter Four: Synthesis of N-Thiopivaloyl Azetidine Organolithium

Reagents ..................................................................................................................... 127

4.1 Lithiation-Trapping of N-Thiopivaloyl Azetidines ........................................ 128

4.1.1 Racemic Lithiation-Trapping of N-Thiopivaloyl Azetidines ....................... 128

4.1.2 Asymmetric Lithiation-Trapping of N-Thiopivaloyl Azetidines ................. 132

4.2 Asymmetric Lithiation-Trapping of N-Thiopivaloyl Azetidine 101 ............. 135

4.2.1 Investigating the Configurational Stability of Lithiated N-Thiopivaloyl

Azetidine ............................................................................................................... 138

4.2.2 Dynamic Resolution of Lithiated N-Thiopivaloyl Azetidine ....................... 145

4.2.3 Lithiation of N-Thiopivaloyl Azetidine 101 and Trapping with Methyl Iodide

............................................................................................................................... 151

4.3 Lithiation-Trapping of N-Thiopivaloyl Pyrrolidine 210 ............................... 159


Pyrrolidine ............................................................................................................. 159

4.3.2 Dynamic Resolution of Lithiated N-Thiopivaloyl Pyrrolidine .................... 162

4.4 Conclusions and Future Work ......................................................................... 164

Chapter Five: Experimental .............................................................................. 167

5.1 General Methods ............................................................................................... 167

5.2 General Procedures ........................................................................................... 168

5.3 Experimental for Chapter Two........................................................................ 173

5.4 Experimental for Chapter Three ..................................................................... 205

5.5 Experimental for Chapter Four ....................................................................... 263

Chapter Six: Abbreviations ................................................................................ 291

Chapter Seven: Bibliography ............................................................................ 294

List of Tables

v

List of Tables

Table 1.1: Lithiation-Boronate rearrangement of O-Alkyl Carbamates ........................... 8

Table 2.1: Optimisation of the Racemic Lithiation of O-Alkyl Carbamate 14 and

Trapping with Andersen’s sulfinate (SS)-97 ................................................................... 49

Table 2.2: Asymmetric Lithiation of O-Alkyl Carbamate 14 and trapping with

Andersen’s Sulfinate (SS)-97 ........................................................................................... 52

Table 2.3: Optimisation of the Sulfoxide → Magnesium Exchange of anti-rac-103 ..... 56

Table 3.1: Oxidation of N-Boc 2-Sulfanyl Pyrrolidines ................................................. 82

Table 3.2: Optimisation of the alkylation of N-benzoyl anisidine 214 ........................... 90

Table 3.3: Asymmetric lithiation-cyclisation of 4-subsituted piperidines ...................... 97

Table 3.4: Optimisation of the racemic lithiation of 4-chloro piperidine 223 and trapping

with sulfinate 121 ............................................................................................................ 98

Table 3.5: Optimisation of the racemic lithiation of N-Boc 4-choro piperidine 223 and

trapping with Andersen’s sulfinate (SS)-97. .................................................................. 101

Table 3.6: Asymmetric lithiation of 4-subsituted piperidines 223, 224 and 234 and

trapping with phenyl isocyanate.................................................................................... 103

Table 3.7: Kinetic resolution of rac-227 ....................................................................... 104

Table 3.8: Asymmetric lithiation of N-Boc 4-chloro piperidine 223 using s-BuLi/chiral

ligands and trapping with phenyl isocyanate ................................................................ 106

Table 3.9: Kinetic resolution of 4-substituted piperidines 223 and 234 ....................... 109

Table 3.10: Investigating the temperature effect on the lithiation-cyclisation of 4-

subsituted piperidine 223 and 234................................................................................. 110

Table 3.11: Lithiation of 4-substituted piperidines 223 and 234 with slow addition of s-

BuLi and trapping with phenyl isocyanate.................................................................... 111

Table 3.12: Lithiation-of 4-substituted piperidines 223 and 234 with slow addition of

starting material and trapping with phenyl isocyanate .................................................. 112

Table 4.1: Asymmetric lithiation-trapping of N-thiopivaloyl azetidine 101................. 133

Table 4.2: Temperature effect on the enantioselectivity of the lithiation-trapping of N-

thiopivaloyl azetidine 101 ............................................................................................. 148

List of Tables

vi

Table 4.3: Asymmetric lithiation-trapping of N-thiopivaloyl azetidine 101 using s-

BuLi/chiral ligands. ....................................................................................................... 150

Acknowledgements

vii

Acknowledgements

The research presented in this thesis would not have been possible without the ideas,

encouragement and scrupulousness of Professor Peter O’Brien. It has been a privilege

to work under his tutelage over the past four years. In addition, I would like to thank

Professor Richard Taylor for his assistance and guidance as my independent panel

member.

I would also like to thank the members of the POB group that I have worked alongside

during my time in York. In no particular order: Xiao, Donald, Giacomo, Graeme, Dave,

Giorgio, Nah, Mary, Alice and Sarah. Thanks also to the additional D215 residents,

Pete and Joe, for the good times and endless supply of glassware. Furthermore, my

thanks go to the Organics football team which has provided a particular highlight of the

week.

I would like to make particular mention of Chris Windle who has shared this whole

experience with me. Through the ups and downs of PhD life, his friendship has helped

me to reach the other side!

This research has benefitted considerably by support from the technical staff within the

Department of Chemistry. Therefore, my sincere thanks go to Steve and Mike from

stores, Heather and Amanda for the excellent NMR service, Trevor and Karl for mass

spectrometry assistance and Graeme for copious amounts of dry solvents. I would also

like to thank Dr Richard Horan, from GlaxoSmithKline, as my industrial supervisor.

He has provided suggestions, support and an enjoyable CASE placement in Stevenage.

I would also like to thank my family, especially Mum and Dad, who have shown me

unending love and support throughout my studies.

Finally, a special thanks to my wife, Sarah, who has always been there for me. More

than anyone else, she has had to put up with the brunt of all the failed reactions yet has

remained loving and full of encouragement throughout.

Author’s Declaration

viii

Author’s Declaration

The research presented in this thesis is, to the best of my knowledge, original except

where due reference has been made to other authors and/or co-workers.

Peter J. Rayner

Chapter One: Introduction

1


Nature shows an astonishing ability to distinguish between the enantiomers of chiral

molecules. Indeed, the mirror image arrangements of a molecule can elicit contrasting

responses in a whole host of biological receptors.1 Therefore, the continued

development of novel synthetic approaches towards diverse three-dimensional

molecules remains of utmost importance to modern society.

Organometallic chemistry offers an attractive technique for the introduction of new

stereogenic centres within complex molecules and has thus become a key part of the

modern synthetic chemist’s armoury. New methods for the synthesis of α-

functionalised organolithium2,3

and organomagnesium reagents are of particular

interest.4,5

In addition to their use in the synthesis of pharmaceutical products,6-8

α-

functionalised organometallics have been used in the stereo-inducing step in a number

of natural product total syntheses, with some recent examples including (−)-kainic acid,9

(−)-swainsonine10

and (−)-decarestrictine D11

(Figure 1.1).

NH

OH

O

OH

O

(_)-Kainic Acid

O

O

HO

OH

OH

(_)-Decarestrictine D

N

OH

H

OH

OH

(_)-Swainsonine

Figure 1.1


2

1.1 Asymmetric Synthesis of α-Functionalised Organolithium Reagents

Organolithium reagents were discovered by Wilhelm Schlenk in 1917.12

The first

synthetic route was an exchange reaction from the mercury derivative forming mercury

amalgam (Scheme 1.1). Schlenk gave vivid descriptions of the organolithium reagents

that were formed, with methyllithium being said to form a “brilliant red flame with a

shower of golden sparks” when exposed to air.13

Et2Hg 2EtLi Li(Hg)3Li

+

Scheme 1.1

Fortunately, the synthesis of organolithium reagents has been significantly improved

over the past century. A contemporary organic chemist would typically synthesise an

organolithium reagent via one of three general methods; transmetallation or halogen-

metal exchange, reductive lithiation of alkyl halides with lithium metal, or

deprotonation/lithiation (Scheme 1.2).

Transmetallation or

Halogen-Metal Exchange Reductive Lithiation Deprotonation/Lithiation

R1X R1Li

R2Li R2X

X = Sn(R3)3, SR4, Br, I

R1X R1Li

2Li LiX

X = Br, I

R1H R1Li

R2Li R2H

Scheme 1.2

For the synthesis of organolithium reagents in an asymmetric fashion, deprotonation

using strong organolithium bases in the presence of chiral ligands is the premier

approach. Significantly, asymmetric deprotonation avoids some mechanistic limitations

of the alternative methods such as difficulties in synthesising secondary organolithium

reagents14

or planar radical intermediates.15

Tin → lithium exchange offers the only

real alternative for the synthesis of chiral organolithium reagents. This methodology

was exemplified by Still and co-workers in 1980.16


3

By far the most important ligand used in asymmetric lithiation is (−)-sparteine, a

naturally occurring chiral diamine (Figure 1.2). It was first used in as a bidentate ligand

in organometallic chemistry in 196817

and since then, it has consistently outperformed

other diamine ligands in terms of yield and enantioselectivity.18

(−)-Sparteine is

extracted from Scotch Broom and is commercially available but more recently, supplies

have been variable. Its enantiomer, (+)-sparteine, is not commerically available. In

2002, our group reported the first readily accessible (+)-sparteine surrogate 1 which

provides enantiocomplementary reactions to (−)-sparteine.19

A review of the chemistry

of the (+)-sparteine surrogate 1 was published in 2008.20

N

NH

HN

NH

(_)-Sparteine (+)-SparteineSurrogate 1

N

NH

H

(+)-Sparteine

Figure 1.2

There are three possible mechanistic pathways that can lead to enantioenriched products

by a lithiation-substitution process. The mechanisms are dictated by the configurational

stability of the organolithium reagent and the relative rates of trapping with

electrophiles. If the organolithium reagent is configurationally stable, then the reaction

will proceed via an enantioselective deprotonation pathway. In contrast, if the

organolithium reagent is configurationally unstable, then the reaction can proceed either

by a dynamic thermodynamic resolution or a dynamic kinetic resolution.

1.1.1 Enantioselective Deprotonation as a Route to Organolithium Reagents

Clayden describes enantioselective deprotonation as ‘conceptually the simplest sort

of asymmetric organolithium reaction’.18

A general enantioselective deprotonation is

depicted in Scheme 1.3. The complex of an organolithium reagent (RLi) and a chiral

ligand (L*) performs an enantioselective deprotonation of substrate 2 to form chiral

organolithium reagent 3. This is the stereo-inducing step and it is essential for the

intermediate organolithium 3 to be configurationally stable under the reaction


4

conditions (typically −78 °C). Organolithium reagent 3 is then trapped by electrophiles

to give enantioenriched products of type 4.

X Y

H H

X Y

H Li.L*

X Y

H ERLi.L* E+

2 3 4

L* = Chiral Ligand

_78 °C

Scheme 1.3

The first enantioselective deprotonation was reported in 1990 by Hoppe et al.21

O-Alkyl

carbamate 5 was treated with s-BuLi/(−)-sparteine in Et2O at −78 °C for 5 hours to give

lithiated intermediate (S)-6 which was then trapped with carbon dioxide or

trimethylsilyl chloride in good yields and enantiomeric ratio (Scheme 1.4). At the time,

Hoppe postulated that activation of carbamate 5 occurred due to chelation and dipole

stabilisation, a phenomenon which was later christened the ‘Complex Induced

Proximity Effect’ (CIPE).22

s-BuLi, (_)-sparteine

Et2O, _78 °C, 5 hO

O

ON O

O

ONMe

H Li

NN

O

O

ONMe

EElectrophile

(R)-7, E = CO2H,75%, >98:2 er

(S)-8, E = SnMe3,

76%, >98:2 erNN = (_)-sparteine

5 (S)-6

N

NH

H

Scheme 1.4

The absolute configuration of (R)-7 was determined by comparison to a known lactic

acid derivative. Crucially, organolithium reagent (S)-6 was configurationally stable

under the reaction conditions16

and trapping proceeded with retention of configuration

at carbon.

In contrast, Hoppe and co-workers reported that the lithiation-trapping of benzylic

carbamate (R)-9 proceeded with either retention or inversion of configuration,

depending on the electrophile employed.23

In this work, (R)-9 (98.5:1.5 er) was treated

with s-BuLi/TMEDA to give organolithium (R)-10. The lithiated intermediate was then


5

either reprotonated or trapped with electrophiles (Schemes 1.5 and 1.6). Reprotonation

by methanol or acetic acid proceeded with retention of configuration to give (R)-9 in

90:10 er. Interestingly, reprotonation by acetic acid was originally reported to proceed

with inversion of configuration however, this has since been corrected.24,25

Ph Li

Me OCb

Ph H

Me OCb

Ph H

Me OCbs-BuLi, TMEDA

Hexane, _78 °C, 30 min

AcOH

MeOH

(R)-998.5:1.5 er

(R)-9, 75%90:10 er

(R)-9, 80%90:10 er

Cb = CONiPr2

(R)-10N

N

TMEDA Ph H

Me OCb

Scheme 1.5

Furthermore, alkylation of (R)-10 with n-propyl bromide or dimethyl carbonate gave

(S)-12 (77%, 92.5:7.5 er) or (R)-13 (85%, 95:5 er) respectively with retention of

configuration. However, the trapping reaction with methyl chloroformate proceeded

with inversion of configuration to give methyl ester (S)-13 in 90% yield and 92.5:7.5 er.

'r etent ion'

'inversion'

Ph Li

Me OCb

Ph CO2Me

Me OCb

Ph H

Me OCb

Ph CO2Me

Me OCbs-BuLi, TMEDA

Hexane, _78 °C, 30 min

MeOCOCl

(MeO)2CO

(R)-998.5:1.5 er

(S)-13, 90%92.5:7.5 er

(R)-13, 85%95:5 er

Cb = CONiPr2

(R)-10

Ph

Me OCb

(S)-12, 77%92.5:7.5 er

n-PrBr

'r etent ion'

Scheme 1.6

For the case of α-oxybenzyl organolithium reagents, Hoppe suggested that the

propensity for the trapping to occur with either retention or inversion of configuration is

due to the close-lying activation energies for front-side and back-side attack. This was

supported by theoretical calculations by Schleyer et al.26

Therefore, the steric demand of


6

the electrophile and the interaction of the leaving group with the lithium ultimately

determine the reaction pathway.

Our group has contributed to the O-alkyl carbamate deprotonation methodology by the

introduction of a catalytic asymmetric variant.27

It was reported that treatment of O-

alkyl carbamate 14 with 2.8 equivalents of s-BuLi in the presence of just 0.2 equivalents

of (−)-sparteine and 1.2 equivalents of achiral diamine 16 and trapping with tributyltin

chloride gave stannane (S)-15 in 60% yield and 97:3 er (Scheme 1.7). The opposite

enantiomeric series was also accessible through the use of the (+)-sparteine surrogate 1,

giving stannane (R)-15 in 86% yield and 96:4 er. The role of achiral diamine 16 is to

displace the chiral ligand from the lithiated intermediate. Thus, the s-BuLi/chiral ligand

complex is then available to deprotonate more O-alkyl carbamate 14. Diamine 16 was a

suitable ligand as its complex with s-BuLi has been shown to be a slow lithiator when

compared to the s-BuLi complexes of (−)-sparteine and (+)-sparteine surrogate 1.28

1. 2.8 eq. s-BuLi, 0.2 eq. (_)-sparteine

1.2 eq. diamine 16, Et2O, _78 °C

2. Bu3SnCl

14

Ph OCb

Cb=CONiPr2

Ph SnBu3

1. 2.8 eq. s-BuLi, 0.2 eq. (+)-sp. surr. 1

1.2 eq. diamine 16, Et2O, _78 °C

2. Bu3SnCl

14

Ph OCb

Cb=CONiPr2

Ph SnBu3

(S)-15, 60%97:3 e.r

(R)-15, 86%96:4 e.r

N

N

16

N

NH

(+)-SparteineSurrogate 1

OCbH

CbO H

Scheme 1.7

The lithiation-trapping of O-alkyl carbamates is a useful method for synthesising α-

substituted protected alcohols in good yield and high enantiomeric ratio. Furthermore,

due to the introduction of the (+)-sparteine surrogate 1, both enantiomers of the

products are accessible.19

In order to access the synthetically desirable secondary

alcohols, removal of the carbamate group would be necessary. This typically proceeds

under harsh reductive conditions (LiAlH4, THF, reflux).29


7

Hoppe developed an alternative approach to secondary alcohols that avoided the need to

use harsh reductive conditions (Scheme 1.8).30

Indeed, lithiation of O-alkyl carbamate

14 and trapping with boronates followed by treatment with Grignard reagents effected

1,2-metallate rearrangement with expulsion of the carbamate moiety. Finally, oxidation

gave chiral alcohols in good yield and high enantiomeric ratio. An example (14 → (S)-

17 → (R)-18) is shown in Scheme 1.8. However, until 2007, there was only one

example of trapping of a lithiated carbamate with a borate ester to give in situ access to

a chiral alcohol in 98:2 er.31

1. s-BuLi, (_)-sparteine

Et2O, _78 °C, 3 h

2. B(Oi -Pr)33. pinacol, p-TsOH,

MgSO4, CH2Cl214

Ph OCb

Cb=CONiPr2

Ph OCb

(S)-1790%, 98:2 er

OB

O

Ph

OH

(R)-1870%, 98:2 er

1. C6H11MgBr

Et2O, _78 °C, 1h

2. H2O2, NaOH

Ph OCb

O B

O

Ph

OB

Ov ia

Scheme 1.8

In 2007, Aggarwal and co-workers reported a general procedure for the trapping of

Hoppe-type lithiated O-alkyl carbamates with boranes and borates and subsequent

conversion into chiral alcohols.32

First, carbamates 14, 19 and 20 were treated with s-

BuLi/(−)-sparteine in Et2O at −78 °C to give the lithiated intermediates. Subsequent

addition of boranes or boronic esters to the lithiated carbamates gave ate-complexes

which furnished secondary alcohols 21-25 via a 1,2-metallate rearrangement and

subsequent oxidation (Scheme 1.9). Selected results are summarised in Table 1.1.

Aggarwal et al. were able to conclude that the reaction of the lithiated carbamates with

both boranes and boronic esters and subsequent 1,2 metallate rearrangement proceeded

with retention of configuration. This supports what was previously reported in the

literature.27,30,33

The configurations of alcohols 21-25 were determined by comparison

to known compounds. Furthermore, the sense of induction in the lithiation of O-alkyl

carbamates using s-BuLi/(−)-sparteine is well established from Hoppe’s work.21


8


Et2O, _78 °C, 5 h

14, R1 = Ph(CH2)219, R1 = Me2C=CH(CH2)

20, R1 = TBSO(CH2)C(Me)2CH2

14, 19 or 20

R1 OCb

Cb=CONiPr2

HH

R1 OCb

Li.(_)-sp.H R2B(R3)2

OCb

B(R3)2

H

R1

R2

B(R3)2

R2

H

R1

OH

R2

H

R1

(LewisAcid)

NaOH/H2O2

21-25

Scheme 1.9

Table 1.1: Lithiation-Boronate rearrangement of O-Alkyl Carbamates

Entry SM R2 (R

3)2 Lewis Acid Product Yield / % er

1 14 Et Et - 21 91 98:2

2 14 Ph 9-BBN - 22 85 88:12

3 14 Ph 9-BBN MgBr2 22 94 97:3

4 19 Et Et - 23 90 97:3

5 19 Et pinacol MgBr2 23 75 97:3

6 20 Et Et - 24 67 95:5

7 20 Ph pinacol MgBr2 25 64 98:2

The methodology was shown to tolerate a number of boranes and boronates. Use of

triethyl borane gave good to excellent yields and excellent enantiomeric ratios in all

cases (entries 1, 4 and 6). Interestingly, in the case of B-Ph-9-BBN, higher er was

obtained in the presence of MgBr2 (entry 3 vs. entry 2), but this was not found to be

necessary in the case of aliphatic groups where high enantioselectivity was observed

without addition of a Lewis acid (entry 1). It was postulated that the addition of MgBr2

sequesters either (−)-sparteine or the carbamate leaving group, thus preventing it from

binding to the borane which would cause homolysis of the benzylic carbon-boron bond.

This would result in a lower enantiomeric ratio of the final alcohol. In addition, this

was the first example of a clean migration of the boron substituent when the leaving

group is not a halide. Finally, pinacol boronates were shown to give good yields (64-

75%) and excellent enantioselectivity (97:3-98:2 er) (entries 5 and 7).


9

Extension of the methodology to include an iterative process with boronic esters

allowed access to scaffolds bearing multiple adjacent stereocentres (Scheme 1.10).

Lithiation of O-alkyl carbamate 14 with s-BuLi/(−)-sparteine gave lithiated intermediate

(S)-26, trapping with ethyl pinacol boronate ester and subsequent 1,2-metallate

rearrangement gave boronic ester (R)-27. A second homologation with lithiated

carbamate (S)-28 gave alcohol (1R,2R)-29 in 82% yield, >98:2 er and 96:4 dr. Alcohol

(1S,2R)-29 was synthesised from boronic ester (R)-27 and lithiated intermediate (R)-28

in good yield (63%) and excellent stereoselectivity (>98:2 er and 96:4 dr). The

enantiocomplementary alcohols (1R,2S)-29 and (1S,2S)-29 were accessed in good yields

and stereoselectivity via lithiation of carbamate 14 with s-BuLi/(+)-sparteine surrogate

1 and electrophilic trapping with ethyl pinacol boronic acid to give boronate (S)-27 and

subsequent homologation with either (S)-28 or (R)-28.

HO

Ph

HO

Ph

HO

Ph

HO

Ph

Ph OCb

Ph OCb

Ph

Ph

B

B

Li

OCb

Li

OCb

Li

OCb

Li

OCb

EtB(pin)

EtB(pin)Ph OCb

Li

Li

s-BuLi,

(_)-sparteine

s-BuLi,(+)-sparteinesurrogate 1

(1R,2R)-29, 82%>98:2 er, 96:4 dr

(1S,2R)-29, 63%>98:2 er, 96:4 dr

(1R,2S)-29, 64%>98:2 er, 96:4 dr

(1S,2S)-29, 63%>98:2 er, 90:10 dr

(S)-26

14

(R)-26

(R)-2778%, 98:2 er

(S)-2775%, 97:3 er

(R)-28

(R)-28

(S)-28

(S)-28

OO

OO

Scheme 1.10

In 2008, Aggarwal and co-workers used the 1,2-metallate rearrangement of boronate

complexes to convert chiral secondary alcohols into tertiary alcohols.34

To prove the


10

concept, carbamate (S)-8 (99:1 er) was deprotonated with s-BuLi in Et2O. Subsequent

addition of the borane or boronic ester followed by oxidation gave the tertiary alcohols

(S)-30 or (R)-30 in excellent yield and enantioselectivity. Two examples are shown in

Scheme 1.11.

Ph

CbO

Ph

Et OH

Ph

CbO

Ph

Et OH

1. s-BuLi, Et2O, _78 °C, 20 min

1. s-BuLi, Et2O, _78 °C, 20 min

2. BEt3,

3. H2O2, NaOH

2. EtB(pin),

3. H2O2, NaOH

(S)-3091%, 99:1 er

(S)-899:1 e.r

(S)-899:1 e.r

(R)-3095%, 99:1 er

H

H

Scheme 1.11

Interestingly, when using boranes the reactions occurred with inversion of

configuration, but the use of boronic esters caused the reaction to proceed with retention

of configuration. Consequently, either enantiomeric series of alcohols can be accessed

starting from (S)-8. Aggarwal suggested that for the case of boronic esters, coordination

between the oxygen of the ester and the lithium of the metalated carbamate causes

delivery on the same face as the metal. As boranes are unable to form the same

complex, reaction occurred on the opposite face to the metal where there is significant

electron density due to a partial-flattening of the carbanion because of its benzylic

nature. This is in contrast to lithiated alkyl carbamates where both boranes and boronic

esters react with retention of configuration due to a sp3-hybridised carbanion which has

very little electron density opposite the metal.

In summary, the lithiation of O-alkyl carbamates, trapping with boranes or boronic

esters and subsequent 1,2-metallate rearrangement, affords chiral secondary and tertiary

alcohols in good yield and excellent enantiomeric ratio. The expediency of the

methodology is highlighted in a number of total syntheses.11,35,36

For example, the

stereo-determining step in the synthesis of (−)-decarestrictine D is shown in Scheme

1.12. Lithiation of O-alkyl carbamate 31 using s-BuLi/(+)-sparteine surrogate 1 and

trapping with tributyltin chloride gave stannane 32 in 72% yield and 97:3 dr. Tin →

lithium exchange of stannane 32 and trapping with silyl vinyl borane 33 gave adduct 34

which underwent 1,2-metallate rearrangement to give 35. Subsequent addition of


11

aldehyde 36 gave cis-alkene 38. This reaction proceeds via the six-membered transition

state 37 in which the alkyl group has to occupy the axial position due to steric

interaction with the boron ligand, thereby giving the Z-double bond. Intermediate 38

was then converted into (−)-decarestrictine D in six steps.11,37

O

O

HO

OH

OH

(_)-Decarestrictine D

CO2Me

OBn

OHOSEM

OCb

SnBu3

OCb

OSEM1. s-BuLi, (+)-sp. surr. 1

Et2O, _78 °C, 1 h

2. Bu3SnCl

SEMO

31 3272%, 97:3 dr

OCb

SiMe3

BSEMOBSEMO

SiMe3

B ORSiMe3

1. n-BuLi,

Et2O, _78 °C, 5 min

2.

SiMe3

B

35 34

OHC

OBn

CO2Me

33

36

Me3Si

38

37

H

SEMO

Scheme 1.12

Enantioselective deprotonation has also been exemplified on a wide array of nitrogen

heterocycles. In 1991, Beak and Kerrick reported the asymmetric lithiation-trapping of

N-Boc pyrrolidine 39 and it has since become the most extensively studied nitrogen

heterocycle.38

Lithiation of N-Boc pyrrolidine 39 using s-BuLi/(−)-sparteine gave chiral

organolithium reagent (S)-40. Subsequent trapping with electrophiles generated α-

substituted pyrrolidines in good yield (55-76%) and high enantioselectivity (≥94:6 er).

For example, silylated pyrrolidine (S)-41 was formed in 71% yield and 97:3 er (Scheme

1.13).

NBoc

39

NLi

s-BuLi

(_)-sparteine

Et2O, _78 °C, 4-6 hNBoc

SiMe3

tBuO O

N

NH

H

= (_)-sparteine

Me3SiCl

H

(S)-40 (S)-4171%, 97:3 er

H

H H

N

NN

N

Scheme 1.13


12

Alternative diamine ligands have also been used to mediate the deprotonation of N-Boc

pyrrolidine 39. For example, lithiation using s-BuLi/diamine (R,R)-42 and trapping

with trimethylsilyl chloride gave (S)-41 in 72% yield and 95:5 er (Scheme 1.14).29

In

addition, the opposite enantiomeric series is also readily available through the use of s-

BuLi/(+)-sparteine surrogate 1.19

Indeed, lithiation of N-Boc pyrrolidine 39 using (+)-

sparteine surrogate 1 as the ligand gave (R)-41 in 84% yield and 95:5 er.

NBoc

SiMe3

H

(S)-4172%, 95:5 er

NBoc

1. s-BuLi, (R,R)-42

Et2O, _78 °C, 3 h

2. Me3SiClNMe

MeN

tBu

tBu

(R,R)-4239

NBoc

SiMe3

H

(R)-4184%, 95:5 er

NBoc

1. s-BuLi, (+)-sp. surr. 1

Et2O, _78 °C, 3 h

2. Me3SiCl N

NH


39

Scheme 1.14

Lithiation of an N-Boc pyrrolidine using s-BuLi/(+)-sparteine surrogate 1 was also used

as a key step in the total synthesis of (−)-kainic acid (Scheme 1.15).9

Treatment of

subsituted pyrrolidine 43 with s-BuLi/(+)-sparteine surrogate 1 and subsequent trapping

with carbon dioxide gave an 81:19 mixture of regioisomeric acids 44 and 45 in 71%

total yield. Elaboration of acid 44 gave (−)-kainic acid in eight steps.

NBoc

H H

H O

OH

NBoc

H H

NH

H H

H O

OH

O

OH

(_)-Kainic Acid

43


THF, _78 °C, 3 h

2. CO2

OMOM OMOM

+

NBoc

H H

OMOM

H

HO

O

4544 71%81:19 mixture

of regioisomersN

NH


Scheme 1.15


13

In 2006, Campos and co-workers reported the synthesis of chiral α-arylated N-Boc

pyrrolidines (Scheme 1.16).39

First, enantioselective deprotonation of N-Boc pyrrolidine

39 using s-BuLi and (−)-sparteine and subsequent transmetallation with zinc chloride

gave organozinc reagent (S)-46. Then, palladium-catalysed Negishi coupling of

organozinc reagent (S)-46 with bromobenzene gave phenyl pyrrolidine (S)-47 in 80%

yield and 96:4 er.

NBoc

1. s-BuLi, (_)-sparteine,

MTBE, _78 °C, 1 h

2. ZnCl2, _78 °C, 30 min NBoc

ZnCl

H

Pd(OAc)2, t -Bu3PHBF4

rt, 16 h

PhBr

NBoc

Ph

H

39 (S)-46 (S)-4780%, 96:4 er

Scheme 1.16

The wide scope of the transmetallation-Negishi methodology has been demonstrated by

O’Brien, Campos et al. and the mechanism was probed by in-situ ReactIR®

spectroscopic monitoring.40

In addition, this type of enantioselective arylation has been

scaled up to produce ~0.6 kg of a glucose kinase inhibitor.6

The enantioselective deprotonation of N-Boc piperidine 48 has also been explored. In

2002, Beak and co-workers reported that lithiation mediated by s-BuLi/(−)-sparteine

and trapping with trimethylsilyl chloride gave α-substituted piperidine (S)-49 in 87:13

er but only 8% yield (Scheme 1.17).41

In addition, enamine 50 was formed as the major

product (43% yield). It was suggested that, due to the very slow rate of deprotonation,

enamine 50 is formed as the product of addition of s-BuLi to the carbonyl of the Boc

group.

NBoc

48

NBoc


Et2O, _78 °C, 16 h

2. Me3SiClSiMe3 N

NH

H

(_)-sparteine

N

50, 43%

H

(S)-498%, 87:13 er

Scheme 1.17


14

In an attempt to solve this problem, a collaboration between the O’Brien and Coldham

groups led to the screening of fourteen chiral ligands for the asymmetric deprotonation

of N-Boc piperidine 48.42

It was shown that increasing the steric bulk of the ligand

dramatically reduced the yield of the lithiation-trapping. However, less sterically

hindered ligands led to reduced enantioselectivity. The highest enantioselectivity was

achieved by using s-BuLi/(R,R)-42 to lithiated N-Boc piperidine 48 and trapping with

trimethylsilyl chloride (Scheme 1.18). From this reaction, silylated piperidine (S)-49

was isolated in 90:10 er but only 13% yield.

NMe

MeN

tBu

tBu

(R,R)-42

NBoc

48

NBoc

1. s-BuLi, (R,R)-42

Et2O, _78 °C, 6 h

2. Me3SiClSiMe3

H

(S)-4913%, 90:10 er

Scheme 1.18

More recently, the first example of a high yielding asymmetric deprotonation of N-Boc

piperidine 48 was reported by our group.43

This lithiation was effected by s-BuLi/(+)-

sparteine surrogate 1. Trapping with trimethylsilyl chloride gave α-substituted

piperidine (R)-49 in 73% yield and 86:14 er (Scheme 1.19).

N

Boc

48

N

Boc

(R)-49, 73%


Et2O, _78 °C, 6 h

2. Me3SiClSiMe3

86:14 er

N

NMe H

(+)-sparteinesurrogate 1

H

Scheme 1.19

This methodology was then applied to a wide range of electrophiles. However, lower

enantioselectivity was noted in trappings with phenyldimethylsilyl chloride, methyl

iodide and dimethyl sulfate. It was speculated that, due to the steric bulk of the lithium-

diamine complex, trapping with these electrophiles only occurred at temperatures where

the organolithium was configurationally unstable.44

Enantioselective deprotonation offers an expedient method for the synthesis of α-

functionalised organolithium reagents. Of particular note is the extensive studies of the


15

lithiation-trapping of O-alkyl carbamates and N-Boc heterocycles but enantioselective

deprotonation has also been conducted on phosphine boranes,45

phosphine sulfides46

and ferrocenes.47

1.1.2 Dynamic Kinetic Resolution of Organolithium Reagents

An alternative method for synthesising chiral organolithium reagents is by a dynamic

kinetic resolution process. If the intermediate α-functionalised organolithium reagent is

configurationally unstable in the presence of a chiral ligand on the timescale of reaction

with the electrophile then the enantiomeric ratio of the products will reflect the rate of

reaction not the ratio of the diastereomeric organolithium complexes. This process is

known as a dynamic kinetic resolution and a general reaction pathway is depicted in

Scheme 1.20.18

The reaction begins by deprotonation of substrate 2 by the complex of

an organolithium reagent (RLi) and a chiral ligand (L*) which leads to the formation of

diastereomeric organolithium reagents (S)-3 and (R)-3. These organolithium reagents

are able to interconvert under the reaction conditions at rate kinv. On addition of an

electrophile (E+), each organolithium reagent will react with a different rate (kS or kR) to

give products (S)-4 and (R)-4. In a dynamic kinetic resolution process, the degree

enantioselectivity is controlled by the difference in energy between the energies of the

transition states of the electrophilic trap, ΔΔG‡.

X Y

H H

X Y

H Li.L*

X Y

H E

RLi.L*

E+

2

(S)-3

X Y

H Li.L*

X Y

H EE+

k inv

kS

kR

(R)-3

(S)-4

(R)-4

k inv > kS , kR

L* = ChiralLigand

Scheme 1.20

In 1994, Beak and co-workers reported the dynamic kinetic resolution of benzylic

organolithium 52 (Scheme 1.21).48

Lithiation of amide 51 by s-BuLi/(_)-sparteine gave

(R)-3

(R)-4

(S)-3

(S)-4

ΔΔG‡


16

diastereomeric organolithium reagents (S)-52 and (R)-52 which were shown to be

configurationally unstable at −78 °C. Upon addition of allyl chloride, trapping occurred

to give (R)-53 in 89% yield and 96:4 er.

O(i -Pr)2N

O(i -Pr)2N

O(i -Pr)2N

kinv

51

Li.(_)-sp

Li.(_)-sp

H

H

O(i -Pr)2NH


pentane, _78 °C

(R)-52

Fast

Slow

O(i -Pr)2NH

(S)-52 (R)-53

(S)-53

89%, 96:4 er

Cl

Cl

Scheme 1.21

Organolithium reagent 52 was shown to be configurationally unstable by a tin →

lithium exchange reaction from enantioenriched stannane (R)-54 (Scheme 1.22).

Treatment of stannane (R)-54 (94:6 er) with s-BuLi in pentane at −78 °C gave

organolithium 52 and trapping with allyl chloride generated (S)-53 in only 52:48 er.

Similarly, in the presence of TMEDA, (S)-53 was isolated in 51:49 er. This reaction

proved that the organolithium reagent was configurationally unstable and the

enantioselectivity could not be attributed to an enantioselective deprotonation event.

O(i -Pr)2NSnBu3H

(R)-54, 94:6 er

s-BuLi, Ligand

pentane, _78 °C

O(i -Pr)2NLi

O(i -Pr)2NH

Cl

Ligand

(S)-53Ligand .

none - 52:48 erTMEDA - 51:49 er

52

Scheme 1.22

In addition, the configurational stability was also evaluated using the Hoffmann test.49-51

The Hoffmann test determines the configurational stability of organolithium reagents on


17

the timescale of reaction with electrophiles. Racemic lithiation of amide 51 (s-BuLi,

pentane, −78 °C) gave racemic organolithium reagent 52. Trapping with racemic amide

rac-55 gave ketone 56 as a 1:1.6 mixture of diastereoisomers. In addition, trapping with

enantioenriched amide (S)-55 also gave ketone 56 in 1:1.6 dr (Scheme 1.23).

O(i -Pr)2N

51

pentane, _78 °C

O(i -Pr)2N

52

Li

N

O

MeO NBn2

N

O

MeO NBn2

s-BuLi

O(i -Pr)2N

NBn2

O(i -Pr)2N

O

NBn2

O

56, 1:1.6 dr

56, 1:1.6 dr

rac-55

(S)-55

Scheme 1.23

Due to the diastereoselectivity of the reactions with racemic and enantioenriched amide

56 being the same, it was concluded that organolithium reagent 52 was

configurationally unstable on the timescale of reactions with the amide electrophile.

Thus, a dynamic kinetic resolution process was occurring. If the diastereoselectivity

had been different then the organolithium reagent would have been configurationally

stable on the timescale of reaction with the amide and a dynamic thermodynamic

resolution process would have been occurring (see Chapter 1.1.3).

Interestingly, the leaving group in the electrophile was revealed to have a dramatic

effect on the enantioselectivity of the lithiation-trapping of 51. Indeed, trapping with

allyl tosylate gave (S)-53 in 94:6 er (Scheme 1.24). This is the opposite enantiomer to

that formed when allyl chloride was used. Beak suggests that this is due to electrophilic

trapping of (S)-52 occurring with inversion due to the change of the leaving group.


18

O(i-Pr)2N

O(i-Pr)2N

O(i-Pr)2N

kinv

51

Li.(_)-sp

Li.(_)-sp

H

H O(i-Pr)2NH


pentane, _78 °C

(R)-52

Fast

Slow

O(i-Pr)2NH

(S)-52

(R)-53

(S)-5346%, 96:4 er

OTs

OTs

Inversion

Scheme 1.24

A dynamic kinetic resolution of N-Boc 2-lithiopiperidine 59 has also been reported by

Coldham et al.52

This is significant due to low yields for the enantioselective

deprotonation of N-Boc piperidine 48 using s-BuLi/(−)-sparteine and other chiral

diamines (see Scheme 1.17). The resolution protocol began with a tin → lithium

exchange on stannane rac-57 in the presence of chiral ligand 58 at −78 °C. Warming

the reaction mixture to −20 °C and slow addition of trimethylsilyl chloride over 50

minutes gave (S)-49 in 71% yield and 94:6 er (Scheme 1.25).

NBoc

SnBu3

NBoc

Li.58

2. _20 °C, 2 min

1. n-BuLi, 58

Et2O, _78 °C, 10 min

NBoc

Li.58

NMe

N

OLi58

Fast

Slow

Me3SiCl

Me3SiCl

NBoc

SiMe3

NBoc

SiMe3

(S)-59

(R)-59 (R)-49

(S)-4971%, 94:6 er

rac-57H H

H H

Scheme 1.25

A dynamic kinetic resolution process can also be carried out directly from N-Boc

piperidine 48 (Scheme 1.26). Racemic lithiation of N-Boc piperidine 48 (s-BuLi,

TMEDA, Et2O, −78 °C, 3 hours) followed by addition of chiral ligand 58 at −20 °C and


19

slow addition of trimethylsilyl chloride over 50 minutes gave silylated piperidine (S)-49

in 60% yield and 95:5 er.

NBoc

NBoc

Li.58

2. 58, _20 °C, 2 min

1. s-BuLi, TMEDA

Et2O, _78 °C, 10 min

NBoc

Li.58

NMe

N

OLi58

Fast

Slow

Me3SiCl

Me3SiCl

NBoc

SiMe3

NBoc

SiMe3

(S)-59

(R)-59 (R)-49

(S)-4960%, 95:5 er

48

H H

H H

Scheme 1.26

Extensive work by Coldham et al. established that this was a dynamic kinetic resolution

process. Unfortunately, high enantiomeric ratios were only achievable with slow

reacting electrophiles. For example, use of tributyltin chloride, DMF or dimethyl

sulfate gave products with little or no enantioselectivity. It was suggested that more

reactive electrophiles are less able to discriminate between the diastereomeric

organolithium reagents.

1.1.3 Dynamic Thermodynamic Resolution of Organolithium Reagents

Another approach to synthesising organolithium reagents in high enantiomeric ratio is

dynamic thermodynamic resolution. If the intermediate organolithium reagent is

configurationally unstable in the presence of a chiral ligand but interconversion of the

diastereomeric complexes does not occur on the timescale of reaction with the

electrophile then the enantiomeric ratio of the products will reflect the ratio of the

diastereomeric organolithium reagents. This process is known as a dynamic

thermodynamic resolution and the organolithium reagents are said to have microscopic

configurational stability (Scheme 1.27).18

The process begins with the complex of an

organolithium reagent (RLi) and a chiral ligand (L*) deprotonating substrate 2 to give

diastereomeric organolithium reagents (S)-3 and (R)-3. These organolithium reagents


20

are able to interconvert under the reaction conditions at rate kinv to give a

thermodynamic ratio of diastereoisomers. When an electrophile (E+) is added, each

organolithium reagent will react with a different rate (kS or kR) to give products (S)-4

and (R)-4. However, because kS and kR are greater than the rate of interconversion of

the diastereomeric organolithium reagents (kinv) the thermodynamic ratio will be

trapped. The enantioselectivity of a dynamic thermodynamic resolution is determined

by the difference in energy between the two diastereomeric lithiated intermediates (ΔG)

and in the presence of an excess of electrophile the enantiomeric ratio of (S)-4 and (R)-4

will directly reflect the diastereomeric ratio of the organolithium intermediates.

X Y

H H

X Y

H Li.L*

X Y

H E

RLi.L*

E+

2

(S)-3

X Y

H Li.L*

X Y

H EE+

k inv

kS

kR

(R)-3

(S)-4

(R)-4

kS , kR > k inv

L* = LigandChiral

Scheme 1.27

An example of this process is shown in Scheme 1.28.53

Lithiation of N-pivaloyl-o-

ethylaniline 60 by s-BuLi in MTBE at −25 °C gave racemic organolithium reagent rac-

61. Cooling the reaction to −78 °C followed by the addition of (−)-sparteine and

trapping with trimethylsilyl chloride gave silylated product (R)-62 in only 56:44 er.

However, if (−)-sparteine was added at −25 °C, incubated at that temperature for 45

minutes and then cooled to −78 °C before trapping with trimethylsilyl chloride, then

silylated product (R)-62 was isolated in a dramatically improved 92:8 er.

(R)-3

(R)-4 (S)-3

(S)-3

ΔG ΔG‡

ΔG‡


21

NH

O

NLi

O

Li NH

O

MTBE_25 °C

1. (_)-sparteine_78 °C, 15 min

2. 2.3 eq. Me3SiCl

(R)-62, 56:44 er

NH

O

NLi

O

Li NH

O

2. _78 °C, 15 min

3. 2.3 eq. Me3SiCl

(R)-62, 92:8 er


rac-61

rac-61

60

60

2 eq. s-BuLi

MTBE_25 °C

2 eq. s-BuLi

H

H

SiMe3

SiMe3

Scheme 1.28

The necessity for a warm-cool cycle to achieve high enantioselectivity indicates that the

diastereomeric lithiated intermediates are interconverting at −25 °C but are not at −78

°C. This is shown schematically in Scheme 1.29. Initially, enantiomeric organolithium

reagents (R)-61 and (S)-61 were present in a 50:50 ratio. Then, (−)-sparteine was added

at −25 °C and diastereomeric organolithium reagents (R)-61.(−)-sp and (S)-61.(−)-sp are

formed. The organolithium reagents then equilibrate to a 92:8 diastereomeric ratio.

This ratio then remained on cooling to −78 °C, a temperature at which the

organolithium reagents are configurationally stable. Addition of an excess of

trimethylsilyl chloride traps the 92:8 mixture of diastereomeric organolithium reagents

and this is reflected in the enantiomeric ratio of the product.

NLi

O

Li NH

O

NLi

O

Li NH

O

_25 °C, 45 min

(R)-61

(S)-61

NLi

O

Li.(_)-sp

NLi

O

Li.(_)-sp

(R)-61.(_)-sp

(S)-61.(_)-sp

NLi

O

Li.(_)-sp

NLi

O

Li.(_)-sp

(R)-61.(_)-sp

(S)-61.(_)-sp

(_)-sparteine _78 °C

Me3SiCl

Me3SiCl

(S)-62

50:

50

(R)-62

92:8

92:8

92:8

H

SiMe3H

SiMe3

Scheme 1.29


22

Finally, Beak and co-workers also showed that it was possible to improve the

enantiomeric ratio of the product be using a deficiency of the electrophile. Thus,

addition of just 0.1 eq. of trimethylsilyl chloride gave silylated product (R)-62 in 99:1 er

but the yield is limited to 10% based on 60 (Scheme 1.30). Such a high

enantioselectivity is a result of a kinetic resolution with organolithium (R)-61.(−)-sp

reacting faster with the electrophile than organolithium (S)-61.(−)-sp, leading to a high

enantioselectivity of the product (R)-62.

MTBE_25 °C

2 eq. s-BuLiNH

O

NLi

O

Li NH

O

2. _78 °C, 15 min

3. 0.1 eq. Me3SiCl

(R)-62, 99:1 er


6160

H SiMe3

Scheme 1.30

The dynamic thermodynamic resolution of N-alkyl and N-allyl-2-lithiopyrrolidines was

reported by Coldham et al. in 2006.52,54

Stannane rac-63 was treated with n-

BuLi/TMEDA in Et2O followed by n-BuLi/64 at −5 °C (Scheme 1.31). After stirring at

−5 °C for 90 minutes, the reaction was cooled to −78 °C and phenylisocyanate was

added. After chromatography, amide (S)-66 was isolated in 56% yield and 96:4 er.

Organolithium reagents (R)-65 and (S)-65 were shown to be configurationally labile at

−5 °C but configurationally stable at −78 °C.

N SnBu3

N Li.64

N

NHPh

O

(S)-6656%, 96:4 er

1. n-BuLi, TMEDA

Et2O, _5 °C

2. n-BuLi, 64_5 °C, 90 min

NOLi

MeN

64

N Li.64

(R)-65

(S)-65

N Li.64

N Li.64

(R)-65

(S)-65

PhNCO_78 °C

rac-63

H H

H

H H

Scheme 1.31


23

The resolution of lithiated pyrrolidine 65 was later expanded by Gawley and co-workers

to include a catalytic dynamic resolution process in the presence of just 0.15 equivalents

of chiral ligand 64.55

In 2008, Coldham reported the dynamic thermodynamic resolution of N-Boc 2-

lithiopiperidine 68.56

Racemic lithiation of N-Boc piperidine 48 using s-BuLi/TMEDA

in Et2O at −78 °C was followed by addition of chiral ligand 67 at −20 °C (Scheme

1.32). The reaction was then incubated at −20 °C for 90 minutes to allow the

equilibration of the diastereomeric lithiated intermediates (S)-68 and (R)-68. Cooling to

−78 °C prevented further interconversion and trapping with trimethylsilyl chloride,

tributyltin chloride or DMF gave silylated piperidine (S)-49 (79:21 er), stannane (S)-57

(80:20 er) or aldehyde (R)-70 (77:23 er) respectively. In contrast to a dynamic kinetic

resolution, a wide range of electrophiles gave similar enantiomeric ratio in the dynamic

thermodynamic resolution process.

NBoc

NBoc

Li.67

2. 67, _20 °C, 90 min

1. s-BuLi, TMEDA

Et2O, _78 °C, 3 h

NBoc

Li.6767

(S)-68

(R)-68

48

NBoc

Li.67

NBoc

Li.67

(S)-68

(R)-68

_78 °C

NBoc

SnBu3NBoc

SiMe3

NBoc

CHO

E+

Me2NN

LiO

(S)-49

51%, 79:21 er

E+ = Me3SiCl

(S)-57

65%, 80:20 er

E+ = Bu3SnCl

(R)-69

54%, 77:23 er

E+ = DMF

H H

H

HHH H

Scheme 1.32

In more recent work, Gawley has reported a catalytic variant of the dynamic

thermodynamic resolution of N-Boc 2-lithiopiperidine 68.57,58

Lithiation of N-Boc

piperidine 48 (s-BuLi/TMEDA, −78 °C, 3 hours) followed by addition of 10 mol% of

chiral ligand 67 at −45 °C presumably gave 10 mol% diastereomeric lithiated

intermediates (S)-68.67 and (R)-68.67 which were able to interconvert (Scheme 1.33).

In order to achieve high enantioselectivity, TMEDA must be able to displace chiral

ligand 67 from the lithiated intermediates without perturbing the thermodynamic ratio

and therefore (R)-68.TMEDA and (S)-68.TMEDA must be configurationally stable at


24

−45 °C. Chiral ligand 67 will then displace TMEDA from the lithiated intermediate

allowing further equilibration of the organolithium reagents. Finally, cooling the

reaction to −78 °C and addition of trimethylsilyl chloride gave silylated piperidine (S)-

49 in 74% yield and 96:4 er. This reaction has been further expanded to include

examples of transmetallation-Negishi coupling.59

NBoc

NBoc

Li.67

2. 10 mol% 67,_45 °C, 3 h

1. s-BuLi, TMEDA

Et2O, _78 °C, 3 h

NBoc

Li.67

67 (S)-68.67

(R)-68.67

48

NBoc

SiMe3

NN

LiO

NBoc

Li.TMEDA

NBoc

Li.TMEDA

(S)-68.TMEDA

(R)-68.TMEDA

TMEDA

TMEDA

67

67

(S)-4974%, 96:4 er

1. _78 °C

2. Me3SiCl

Li

H H

H H

H

Scheme 1.33

To conclude, dynamic thermodynamic resolution can be used to synthesise chiral

organolithium reagents which are than reacted with electrophiles to give substituted

products. The enantiomeric ratio of the products is dependent upon the thermodynamic

ratio of diastereomeric organolithium reagents. Unlike a dynamic kinetic resolution

process, the enantioselectivity does not vary significantly between electrophiles

allowing for a wide scope of products to be formed.


25

1.2 Asymmetric Synthesis of α-Functionalised Organomagnesium

Reagents

Since their preparation by Victor Grignard in 1900,60,61

organomagnesium reagents have

become ubiquitous within organic chemistry. The classic preparation of Grignard

reagents – as they would later become known – is the oxidative insertion of magnesium

into carbon-halogen bonds (Scheme 1.34). It is generally accepted that this reaction

proceeds via a radical pathway.62,63

R X R MgXMg

THF or Et2O

Scheme 1.34

The induction period for the insertion is typically dependent on the amount of moisture

present and the nature of the surface of the magnesium turnings. Therefore, a number

of chemical activation procedures have been developed, such as the addition of iodine,64

1,2-dibromoethane65

and diisobutylaluminum hydride.66

In addition, physical activation

procedures have also been utilised (e.g. dry stirring magnesium turnings under an inert

atmosphere67

and removal of metal oxides from the surface of magnesium turnings68

).

In 1929, Schlenk described the chemical equilibrium taking place within ethereal

solutions of Grignard reagents (Scheme 1.35).69

The equilibrium exists between 2 eq. of

the alkyl or aryl magnesium halide and 1 eq. the dialkyl or diaryl magnesium species

and the magnesium halide salt. The position of the equilibrium can be dependent upon

temperature, solvents and additives such as [15]-crown-5 or 1,4-dioxane.70,71

RMgX R2Mg + MgX22

Scheme 1.35

Knochel and co-workers have also reported the syntheses of the more reactive dialkyl or

diaryl magnesium species without the need for manipulation of the Schlenk equilibrium


26

(Scheme 1.36).71

Addition of an alkyllithium reagent to an alkyl magnesium halide

gives the dialkylmagnesium lithium halide complex by a transmetallation process.

RMgCl + RLi R2Mg.LiCl

Scheme 1.36

Despite the common use of Grignard reagents in organic synthesis, there are very few

methods for synthesising enantioenriched α-functionalised Grignard reagents reported

in the literature. Two such methods are transmetallation of chiral organolithium

reagents and sulfoxide → magnesium exchange of enantioenriched sulfoxides.

1.2.1 Asymmetric Synthesis of Grignard Reagents by Lithium → Magnesium

Transmetallation

Chiral Grignard reagents can be synthesised by transmetallation of enantioenriched

organolithium reagents. In 2001, Nakai and co-workers described the transmetallation

of lithiated O-alkyl carbamates using MgBr2 (freshly prepared from 1,2-dibromoethane

and magnesium metal) to give enantioenriched Grignard reagents.72

Treatment of

organolithium (S)-26 (formed by tin → lithium exchange) with MgBr2 gave Grignard

reagent (S)-70 (Scheme 1.37). Subsequently, the reaction was warmed to room

temperature for 1 hour and then cyclohexenone was added. From the reaction, alcohols

(R)-71 were isolated in 44% yield as a 79:21 mixture of diastereoisomers.

Hydrogenation of (R)-71 established the absolute configuration and enantiomeric ratio

(95:5 er) by comparison with a known compound. The transmetallation and trapping

was shown to proceed with retention of configuration from organolithium (S)-26. When

compared to organolithium (S)-26, Grignard reagent (S)-70 shows remarkable

configurational and chemical stability up to room temperature. In contrast, (S)-26

undergoes 1,2-carbamoyl migration at −20 °C.73

Li

CbO

Ph MgBr

CbO

Ph

CbO

Ph

HO

(R)-71, 44%95:5 er, 79:21 dr

O2.

1. rt, 1 hMgBr2

(S)-26, 95:5 er (S)-70, 95:5 er

THF_78 °C, 1 h

H H H

Scheme 1.37


27

A similar approach was used in our group to synthesise chiral α-amino Grignard

reagents.74

Transmetallation of organolithium reagent (S)-40 (formed by

enantioselective deprotonation of N-Boc pyrrolidine 39 using s-BuLi/(−)-sparteine) with

MgBr2 gave Grignard reagent (S)-72 (Scheme 1.38). The reaction was then warmed to

0 °C for 30 minutes and addition of benzaldehyde gave a 70:30 mixture of

diastereomeric alcohols anti-(S,R)-73 and syn-(R,R)-73 in 96:4 and 97:3 er respectively.

Interestingly, when the organolithium reagent was trapped with benzaldehyde, syn-

(R,R)-73 was formed as the major diastereoisomer (75:25 dr).

NBoc

Ph

OH

H

NBoc

Ph

OH

H

NBoc

Li

H

NBoc

MgBr

H 1. 0 °C, 30 min

2. PhCHO

anti-(S,R)-7356%, 96:4 er

syn-(R,R)-7317%, 97:3 er

MgBr2

Et2O, _78 °C

30 min

(S)-40 (S)-72

Scheme 1.38

The configurational stability of Grignard reagent (S)-72 was remarkable when compared

to organolithium reagent (S)-40. The Grignard reagent was shown to be

configurationally stable at 0 °C for at least 30 minutes, whereas the organolithium

reagent is known to be configurationally labile at temperatures above −40 °C.75,76

The limitation of synthesising Grignard reagents by transmetallation of organolithium

reagents is that the enantiomeric ratio of the products is dependent upon the

enantioselectivity of the formation of the organolithium. Therefore, it may not be

possible to access an array of α-alkoxy and α-amino Grignard reagents in ≥99:1 er using

this method. Of significant note, however, α-alkoxy and α-amino Grignard reagents

show increased configurational stability when compared to their organolithium

counterparts.

1.2.2 Asymmetric Synthesis of Grignard Reagents by Sulfoxide → Magnesium

Exchange

Since its discovery in 1962,77

the sulfoxide → magnesium exchange reaction has been

widely applied to the synthesis of enantiomerically pure sulfoxides. However, its use to

form Grignard reagents has been given significantly less attention.4 To this end, the


28

groups of Satoh, Knochel and Hoffmann have been the pioneers of sulfoxide → metal

exchange reactions over the past two decades. Initially, much effort was given to the

investigation of sulfoxide → lithium exchange as a method to synthesise chiral N-aryl

aziridines, epoxides, allylic alcohols and α-amino carbonyls.78,79

However, in 1988,

Satoh reported the use of sulfoxide → magnesium exchange chemistry to synthesise N-

aryl aziridines.78,80

A general reaction between an alkyl aryl sulfoxide 74 and a

Grignard reagent to give either an alkyl Grignard reagent 75 or an aryl Grignard reagent

76 is shown in Scheme 1.39. The structure of sulfoxide 74 and relative stabilities of the

Grignard reagents 75 and 76 determine which of these routes is preferred.81

ArS

R

OAr

SR'

O

R'S

R

O

RMgX

ArMgX

R'MgX

74

75

76

Scheme 1.39

Sulfoxide → magnesium exchange has been proved to be an expedient method for

synthesising sp2

hybridised Grignard reagents.82

Selected examples of efficient

sulfoxide → magnesium exchange include 1-halovinyl sulfoxides,81,83

pyridyl and

quinolyl sulfoxides,84

meta- and para-difunctionalisation of arenes85,86

and 2,3-

funtionalisation of furans, benzofurans and thiophenes.87

Sulfoxide → magnesium exchange reactions that yield chiral Grignard reagents are of

most relevance to the work described in this thesis. Indeed, there are limited alternatives

to synthesise sp3 hybridised Grignard reagents. One example of note is alkoxide

directed iodine → magnesium exchange.88

In 1989, Satoh and co-workers reported the synthesis of chiral N-aryl aziridines via

sulfoxide → magnesium exchange (Scheme 1.40).80

Treatment of sulfoxide (R,R,RS)-77

with EtMgBr gave chiral Grignard reagent (S,R)-78 which was trapped with EtOH to

give aziridine (S,R)-79 in 95% yield. The reaction proceeds by attack of EtMgBr on the

sulfoxide with displacement of the most stable anion, metalated aziridine (S,R)-78 in

this case. The authors report no observable loss of enantiomeric ratio under the reaction

conditions, as determined by optical rotation.


29

N

Ph

Me Ph

S H

O

N

Ph

Me Ph

BrMg H

N

Ph

Me Ph

H

EtMgBr

_55 °C, 2 h

(S,R)-79, 95%(R,R)-78(R,R,RS)-77

H

EtOHpTol

Scheme 1.40

The synthesis of chiral Grignard reagents was further developed by Hoffmann and co-

workers during the 1990s.89,90

In 1999, Hoffmann and Neil reported the synthesis of α-

chloro alkyl organomagnesium reagents in >95:5 er via sulfoxide → magnesium

exchange (Scheme 1.41).90

α-Chloro sulfoxide (R,RS)-80 (98.5:1.5 er) was treated with

EtMgBr at −78 °C to give α-chloro Grignard reagent (R)-81. Grignard reagent (R)-81

was then trapped with α-aminomethyl benzotriazole 82 to give chloro amine (R)-83 in

50% yield and 96.5:3.5 er. The full versatility of this methodology was exemplified in

2000.91

S

O

Cl

Ph

MgBr

Cl

PhEtMgBr

THF, _78 °CN

Cl

PhPh

N

NN

N

Ph

(R,RS)-80, 98.5:1.5 er (R)-81 (R)-8350%, 96.5:3.5 er

82

Scheme 1.41

In addition, Blakemore and co-workers have utilised the sulfoxide → magnesium

exchange reaction to conduct a stereospecific reagent-controlled homologation starting

from α-chloro sulfoxides (Scheme 1.42).92

Trapping of Grignard reagent (S)-81

(generated by sulfoxide → magnesium exchange from (R,RS)-80) with Ph(CH2)2B-

dioxaborinane followed by metallate rearrangement and oxidation (H2O2, NaOH) gave

alcohol (S)-84 in 49% yield and 91:9 er. The authors noted that the disappointing

stereochemical control in the reaction could be improved by using organolithium

reagents.


30

S

O

Cl

Ph Ph

MgCl

Cl

PhMe_78 °C, 30 min

EtMgCl

Ph

OH

Ph

O

B

OPh

2. H2O2, NaOH

EtOH-THF, 0 °C

1.

(S)-8449%, 91:9 er

(R,RS)-80, 99:1 er (S)-81

Scheme 1.42

In more recent work from the Satoh group, chiral α-chloro sulfoxides have also been

used to synthesise cyclic α-amino acid derivatives via sulfoxide → magnesium

exchange.93

t-BuMgCl was added to sulfoxide (S,RS)-85 in order to deprotonate the

aniline moiety and then addition of i-PrMgCl facilitated a sulfoxide → magnesium

exchange to give adduct 86 (Scheme 1.43). Subsequent cyclisation to give Grignard

reagent (S)-87 and trapping with ethyl chloroformate gave (R)-88 in 66% yield and 99:1

er.

NH

Me

Cl

S

O

pTol

(S,RS)-85, 99:1 er

NMe

O

OEt

(R)-8866%, 99:1 er

via

N

Me

Cl

MgCl

1. t -BuMgCl

Toluene, _40 °C, 5 min

2. i-PrMgCl, _40 °C, 5 min

3. EtOCOCl

MgCl

86

NMe

MgCl

(S)-87

Scheme 1.43

In 1999, Knochel et al. reported the synthesis and trapping of α-alkoxy Grignard reagent

90 from sulfoxide 89 (Scheme 1.44).94

Sulfoxide → magnesium exchange mediated by

i-PrMgBr (THF, −78 °C, 15 minutes) gave Grignard reagent 90 and trapping with

benzaldehyde gave alcohol anti-91 in 61% yield and 93:7 dr.


31

PivO MgBr

Me

PhPivO

Me

OH

PhCHO, Me3SiCl

THF, _78 °C to rtTHF, _78 °C, 15 min

i-PrMgBrPivO S

Me

Ph

O

89 90 ant i-9161%, 93:7 drPiv =

O

Scheme 1.44

Palladium-catalysed cross coupling of Grignard reagents formed by sulfoxide →

magnesium exchange has also been reported. In 2003, Hoffmann and Hӧlzer reported

the Kumada-Corriu95,96

coupling of Grignard reagents derived from a sulfoxide →

magnesium exchange (Scheme 1.45).97

α-Chloro sulfoxide (S,RS)-80 was treated with 5

eq. of EtMgCl at −78 °C to give Grignard reagent (S)-92 (which had previously been

shown to be configurationally stable at −78 °C). Subsequent Kumada-type coupling

with vinyl bromide gave the coupled product (S)-93 in an optimised 60% yield and 94:6

er. This represents essentially full retention of configuration from Grignard reagent (S)-

92.

Cl

SPh

O

MgCl

Ph Ph5 eq. EtMgCl

THF, _78 °C 10 mol% NiCl2(dppf)

THF, _78 °C, 5 d

(S,RS)-80, 95:5 er (S)-92, 95:5 er (S)-9360%, 94:6 er

Br

Scheme 1.45

The major limitation of the Kumada-Corriu coupling as reported by Hoffmann is the

need for extremely long reaction times (5 days) at −78 °C. One way to circumvent this

problem is to conduct a transmetallation-Negishi coupling of the Grignard reagent.

Indeed, Bull et al. reported the palladium-catalysed cross-coupling of aziridinylmetal

species generated from sulfoxide → magnesium exchange in 2013 (Scheme 1.46).98

Treatment of sulfoxide 94 (synthesised in three steps from ethyl p-tolyl sulfoxide99

)

with i-PrMgCl in THF at −78 °C gave Grignard reagent 95. Subsequent in situ

transmetallation of 95 with zinc chloride and Negishi coupling gave phenyl aziridine 96

in 80% yield.


32

N

S H

Me Ph

PMP

N

ClMg H

Me Ph

PMP

N

Ph H

Me Ph

PMP

96, 80%

O

pTol

94 95

PhBr, Pd2(dba)3.CHCl3

t-Bu3P, ZnCl2, THF, rt, 15 h

i-PrMgCl

THF, _78 °C

Scheme 1.46

To conclude, sulfoxide → magnesium exchange provides an expedient method for

synthesising chiral Grignard reagents. However, only two examples of sulfoxide →

magnesium exchange giving α-amino Grignard reagents in high enantiomeric ratio have

been reported. Much attention has been focused on the synthesis of α-chloro Grignard

reagents and their application in synthesis. Currently, there have been no examples

reported of sulfoxide → magnesium exchange reactions being conducted at

temperatures higher than −40 °C.


33

1.3 Project Outline

The aim of the research described in this thesis is to develop novel methods for

synthesising chiral α-alkoxy and α-amino organometallic reagents. Two approaches

will be taken; (i) synthesis of α-alkoxy and α-amino Grignard reagents by sulfoxide →

magnesium exchange (Chapters Two and Three) and (ii) asymmetric lithiation of N-

thiopivaloyl azetidine and pyrrolidine (Chapter Four).

Asymmetric lithiation of O-alkyl carbamates and N-Boc heterocycles using s-

BuLi/chiral ligands is typically performed at low temperatures (−78 °C) for long

reaction times (1-6 hours). In addition, products are typically formed in ≤99:1 er. To

address these limitations, we propose that enantiopure sulfoxides can be used as

precursors for chiral Grignard reagents (Scheme 1.47). The Grignard reagents will be

formed via sulfoxide → magnesium exchange, which will ideally take place at

temperatures of 0 °C or above making it amenable to industrial-scale synthesis.

Furthermore, we will particularly focus on substrates where asymmetric deprotonation

chemistry cannot access organolithium reagents in ≥99:1 er. The results of this project

are presented in Chapter Two (α-alkoxy Grignard reagents) and Chapter Three (α-amino

Grignard reagents).

R H

XH

R Li

XH

R E

XH

s-BuLi, Ligand

Et2O, _78 °C, 1-6 h

Electrophile (E+)

X = OCb, NR'Boc

Cb = CONiPr2

R S

X

R MgCl

XH

R E

XH

THF, >0 °C, <30 min

Electrophile (E+)i-PrMgClAr

O Ar = p-Tol

AsymmetricLithiation

Sulfoxide

MagnesiumExchange

99:1 dr, 99:1 er 99:1 er 99:1 er

99:1 er 99:1 er

Scheme 1.47

We believe that this methodology will provide significant benefits over asymmetric

lithiation chemistry not least because the availability of (−)-sparteine has been variable

during the course of the research described in this thesis. This is of much concern as

(−)-sparteine generally gives the highest enantioselectivity over a wide range of reaction


34

types. The plan was that the enantiopure sulfoxides would be synthesised by lithiation

of the corresponding O-alkyl carbamates or N-Boc heterocycles and trapping with

Andersen’s sulfinate (SS)-97 (Scheme 1.48). Subsequent sulfoxide → magnesium

exchange would give access to the corresponding Grignard reagents. This would mean

that one lithiation-trapping reaction would give access to an array of products in ≥99:1

er.

R H

XH

R Li

Xs-BuLi, Ligand

Et2O, _78 °C, 1-6 h

X = OCb, NR'Boc

Cb = CONiPr2

R S

X

pTol

O

99:1 er

R S

X

pTol

O

99:1 er

SO

O(SS)-97

(SS)-97

Scheme 1.48

One example of the use of sulfoxides as chiral auxiliaries in this way is shown in

Scheme 1.49. In 2001, Johannsen and co-workers reported the use of a sulfoxide →

lithium exchange as a route to optically pure azaferrocenyls.100

Ortho-lithiation of

azaferrocene 98 by n-BuLi followed by addition of Andersen’s sulfinate (SS)-97 gave

diastereomeric sulfoxides (SS,SP)-99 and (SS,RP)-99 in 29% yield and 33% yield

respectively, both in ≥99:1 er. These are essentially enantiomeric ferrocenyl anion

equivalents.

SO

O

(SS)-97

N

Fe1. 1.1 eq. n-BuLi, THF, 0 °C

2. 1.2 eq. N

Fe

N

Fe

S SpTolpTol

O O

(Ss,Sp)-99

29%, 99:1 er(Ss,Rp)-99

33%, 99:1 er

98

Scheme 1.49

The authors then treated sulfoxide (SS,SP)-99 with t-BuLi in THF at −78 °C to achieve a

sulfoxide → lithium exchange. Subsequent trapping of the lithiated intermediate with

iodine gave iodide (SP)-100 in 52% yield and ≥99:1 er (Scheme 1.50). In addition,

enantiomeric iodide (RP)-100 was synthesised in similar fashion from sulfoxide (SS,RP)-

99 in 68% yield and ≥99:1 er.


35

N

Fe

S

O

(Ss,Sp)-99

1. 2.5 eq. t-BuLi, THF, _78 °C

2. 2.5 eq. I2, _78 °CpTol

N

Fe

I

(Sp)-100

52%, 99:1 er

N

Fe

SpTol

O

(Ss,Rp)-99

1. 2.5 eq. t-BuLi, THF, _78 °C

2. 2.5 eq. I2,_78 °C

N

Fe

(Rp)-100

68%, 99:1 er

I

Scheme 1.50

We propose that the use of sulfoxide → magnesium exchange would provide significant

benefits. Not only does the use of Grignard reagents deliver a safety benefit

(particularly if this chemistry is to become available to the industrial chemist), but chiral

α-substituted Grignard reagents have been shown to have a higher degree of

configurational stability than their organolithium counterparts.72,74

This should allow

our proposed methodology to be conducted at ambient temperatures.

In Chapter Four, an investigation into the asymmetric lithiation-trapping of N-

thiopivaloyl azetidine 101 is presented. Despite their importance as bioactive

compounds, novel methods for synthesising substituted chiral azetidines have received

limited attention from the academic community.101

One approach is the lithiation of N-

thiopivaloyl azetidine 101 using s-BuLi and chiral diamines although only one example

has been reported in the literature (Scheme 1.51).102

Lithiation of 101 using s-

BuLi/(R,R)-42 and trapping with methyl iodide gave methylated azetidine (R)-102 in

96% yield and 80:20 er

N

S 2. MeI

1. s-BuLi, (R,R)-40

Et2O, _78 °C, 30 min

101

N

S

(R,R)-42

HN

N

tButBu

(R)-10296%, 80:20 er

Scheme 1.51


36

To our surprise, lithiation of N-thiopivaloyl azetidine 101 proceeded with the opposite

sense of induction to that observed for the asymmetric lithiation of N-Boc pyrrolidine

3938

and N-Boc piperidine 4841

. The authors offered no explanation for the differing

enantio-induction between these examples but suggested that a directed enantioselective

deprotonation may take place.

Our aim was to identify the mechanism by which asymmetric lithiation-substitution

occurs. Therefore, a detailed mechanistic study of this reaction was undertaken and is

described in Chapter Four.


37

Chapter Two: Synthesis and Reactions of α-Alkoxy

Grignard Reagents

Our goal was to synthesise enantiopure α-alkoxy Grignard reagents and exemplify their

reaction profile. The plan was twofold. First, the intention was to synthesise

diastereomeric sulfoxides anti-(S,SS)-103 and syn-(R,SS)-103 in ≥99:1 er (Scheme 2.1).

It was envisaged that an expedient route would be via lithiation-trapping of O-alkyl

carbamate 14, with the α-alkoxy stereocentre being controlled by a chiral base and the

sulfoxide stereocentre arising from Andersen’s sulfinate (SS)-97.

SPh

O

SPh

CbO H

O

CbO H

ant i-(S,Ss)-103 syn-(R,Ss)-103

Ph OCb SO

O

(SS)-9714Cb = CONiPr2

Scheme 2.1

Second, a sulfoxide → magnesium exchange procedure would then be developed to

allow access to either enantiomer of Grignard reagent 104 in ≥99:1 er, hopefully under

ambient conditions (Scheme 2.2). Subsequent electrophilic trapping would generate α-

substituted products in ≥99:1 er. Our efforts towards these aims are described in this

chapter.

SPh

O

SPh

CbO H

O

CbO H

anti-(S,Ss)-103

syn-(R,Ss)-103

Ph

CbO H

MgCl

Ph

CbO H

MgCl

(S)-104

(R)-104

i-PrMgCl

THF0 °C

i-PrMgCl

THF0 °C

Scheme 2.2


38

2.1 Previous Syntheses of α-Alkoxy Sulfoxides

Three different approaches for the synthesis of α-alkoxy sulfoxides have been reported

in the literature. Each method requires a late-stage sulfide oxidation to yield the target

molecule. First, Nozaki and co-workers reported the synthesis of sulfoxides anti-107

and syn-107 en route to isomeric alkenes cis-108 and trans-108 (Scheme 2.3).103

This

strategy began with the lithiation-trapping of sulfide 105 and subsequent acetylation to

give sulfides anti-106 and syn-106. Subsequent m-CPBA oxidation of anti-106

furnished sulfoxide anti-107 which was isolated before elimination at high temperature

to give alkene cis-108 in 50% yield over two steps. A similar procedure was used to

convert sulfide syn-106 into alkene trans-108.

2. Ac2O, py. rt, 16 h

CH2Cl20 °C, 1 h

OMe

SPh

OMe

SPh

AcO

Ph

OMe

SPh

AcO

Ph

1. n-BuLi, PhCHO,

THF, _78 °C, 3 h

m-CPBA OMe

S

AcO

Ph

OMe

S

AcO

Ph

105

anti-106, 52%

syn-106, 21%

ant i-107

syn-107

100 °CPh

AcO

H

OMe

Ph

AcO

OMe

H

t rans-108,60% over two steps

cis-108,50% over two steps

100 °CCH2Cl20 °C, 1 h

m-CPBA

Ph

O

O

Ph

PhMe

PhMe

Scheme 2.3

In 1999, Knochel et al. reported the synthesis of α-alkoxy sulfoxide 89.94

The strategy

began with chlorination of ethyl sulfide 109 using N-chlorosuccinimide. This gave

chlorosulfide 110 in 86% yield. Nucleophilic addition of pivalic acid to chlorosulfide

110 followed by oxidation using mCPBA gave sulfoxide 89 in 62% yield over two steps

(Scheme 2.4).

S Cl S

MeMe

O S

Me

O

CH2Cl2, rt, 2 h

NCS

DBU, PhMe, 10 h

2. mCPBA, CH2Cl2_30 °C, 30 min

109 110, 86% 89, 62%

OOH

O

1.

Scheme 2.4


39

Finally, Yoshimura et al. have reported the synthesis of α-alkoxy sulfoxides via a

Pummerer rearrangement and subsequent oxidation (Scheme 2.5).104

Refluxing ethyl

phenyl sulfoxide 111 in acetic anhydride gave sulfide 112 in poor yield (8%). mCPBA

oxidation of sulfide 112 gave sulfoxide 113 although the yield for this step was not

reported.

S

O

S

OAc

S

OAc

O

Ac2O

reflux, 3 h

m-CPBA

CH2Cl2, 0 °C 2 h

112, 8% 113yield not reported

111

Scheme 2.5

None of the reported approaches to α-alkoxy sulfoxides control the sulfoxide

configuration. Indeed, the use of oxidation chemistry to access sulfoxides provides a

limitation when extending the methodology to encompass the synthesis of

enantiomerically pure sulfoxides. Typically, asymmetric oxidation of sulfides gives

products with varying enantioselectivity. The most useful protocol was published by

Kagan et al. in 1984 and involved use of a modified Sharpless reagent which proceeds

in 85:15-95:5 er (Scheme 2.6).105

For example, when methyl p-tolylsulfide 114 was

treated with Ti(Oi-Pr)4, (R,R)-diethyl tartrate, water and t-BuOOH, sulfoxide (R)-115

was formed in 90% yield and 95:5 er. In limited examples, recrystallisation can afford

sulfoxides in 99:1 er.106

OH

HO

O

EtO

O

OEt

(R,R)-DET

S

O

S

114

Ti(Oi-Pr)4, (R,R)-DETH2O, t-BuOOH

CH2Cl2, _20 °C, 4 h

(R)-11590%, 95:5 er

Scheme 2.6

Other reported methods for asymmetric sulfide oxidation include the use of chiral

peracids and oxaziridines (<60:40 er),107

electrochemical oxidation (78:22 er)108

and

oxidation using micro-organisms (<99:1 er).109

However, none of these methods

provides an improvement on the Kagan protocol.


40

An alternative approach to synthesise enantiopure sulfoxides is the use of sulfinyl

transfer reagents. In 1962, Andersen reported the first synthesis of an enantiomerically

pure sulfoxide from an enantiomerically pure sulfinate by addition of a Grignard reagent

(Scheme 2.7).110

Sulfinate (SS)-97 was first synthesised by Phillips et al. in 1926 from

(−)-menthol and p-toluenesulfinyl chloride in 44% yield after two recrystallisations.111

Andersen treated sulfinate (SS)-97 with EtMgBr to give ethyl p-tolylsulfoxide (R)-116

in 64% yield.

HO OS

O

(SS)-97, 44%

S

O

(R)-116, 64%

EtMgBr

Et2O, 0 °C

pTolS(O)Cl

pyridine

Scheme 2.7

Later, Andersen used this method to synthesise a number of enantiomerically pure

sulfoxides.77,112

Detailed mechanistic studies have also shown that the nucleophilic

addition to sulfinates and sulfoxides occurs with inversion of configuration at

sulfur.113,114

Whilst Andersen’s sulfinate (SS)-97 remains the archetypal precursor for the synthesis

of chiral sulfoxides, other sulfinyl transfer reagents have been reported in the literature

(Figure 2.1). In 1992, Alcudia and co-workers reported the synthesis of the sulfinate

ester of diacetone-D-glucose (SS)-117.115

Addition of Grignard reagents to sulfinate

(SS)-117 furnished an array of sulfoxides as single enantiomers.

ON OS

TsN

Ph Ph

O

S

O O

(SS)-118 (SS)-119

O

OO

O

O

O

S

O

Me

(SS)-117

Figure 2.1

In the same year, Evans et al. reported the synthesis and reactions of N-sulfinyl

oxazolidinone (SS)-118 to form chiral sulfoxides.116

More recently, Stockman and co-


41

workers described the synthesis of oxathiazolidine oxide (SS)-119 from L-phenylalanine

and thionyl chloride.117,118

Oxathiazolidine oxide (SS)-119 has been used to form single

enantiomers of sulfoxides, sulfonamides and sulfinimines.

To conclude, none of the reported methods offer a convenient approach to the synthesis

of α-alkoxy sulfoxides as single enantiomers. However, modifications could be made to

include an asymmetric sulfide oxidation of which the Kagan protocol would offer the

best method. An alternative route to chiral sulfoxides would be the addition of

organometallic reagents to sulfinyl transfer reagents although, prior to the work

described in this thesis, this chemistry has not yet been applied to α-alkoxy sulfoxides.


42

2.2 Synthesis of α-Alkoxy Sulfoxides

We envisaged that sulfoxides anti-(S,SS)-103 and syn-(R,SS)-103 would be synthesised

by lithiation chemistry from O-alkyl carbamate 14 and Andersen’s sulfinate (SS)-97 as

outlined in Scheme 2.8. Lithiation of O-alkyl carbamate 14 mediated by s-BuLi and a

diamine and then trapping with inversion of configuration at sulfur with Andersen’s

sulfinate (SS)-97 would allow rapid access to the desired sulfoxides without the need to

use asymmetric oxidation chemistry. It was hoped that use of a chiral diamine would

allow access to the major diastereoisomer in high yield.

OCbPh

1. s-BuLi, diamine

Et2O, _78 °C

2.

anti-(S,Ss)-103 syn-(R,Ss)-10314

SPh

CbO H

O

SO

O

(Ss)-97

Cb = CONiPr2

SPh

CbO H

O

Scheme 2.8

2.2.1 s-BuLi/TMEDA-Mediated Lithiation of O-Alkyl Carbamates and Trapping

with Andersen’s Sulfinate

First, the racemic synthesis of sulfoxides anti-rac-103 and syn-rac-103 was required in

order to provide standards for CSP-HPLC analysis. Therefore, O-alkyl carbamate 14

was synthesised using a method previously reported by our group.29

3-Phenyl propanol

was deprotonated using sodium hydride and diisopropylcarbamoyl chloride was added

to give the desired carbamate 14 in 88% yield (Scheme 2.9).

OPh

14, 88%

OHPh1. NaH, Et2O, rt, 5 min

N

O

2. i-Pr2NCOCl, rt, 16 h

Scheme 2.9


43

In addition, methyl p-tolyl sulfinate 121 was synthesised in 88% yield by oxidation of

p-tolyl disulfide 120 with bromine in methanol (Scheme 2.10).119

This would be used

as the electrophile in the lithiation-trapping of O-alkyl carbamate 14 before

investigating the trapping with Andersen’s sulfinate (SS)-97.

SS

SOMe

O

Br2, Na2CO3

MeOH, rt, 3 h

121, 88%120

Scheme 2.10

Lithiation of O-alkyl carbamate 14 with 1.2 eq. of s-BuLi/TMEDA at −78 °C and

trapping with methyl p-tolyl sulfinate 121 gave sulfoxides anti-rac-103 and syn-rac-103

in 25% and 32% yield respectively (Scheme 2.11). Importantly, the two

diastereoisomers were readily separable by column chromatography and had distinctive

1H and

13C NMR spectra. The OCH signals for sulfoxide anti-rac-103 were δH 5.45

(doublet of doublets, J = 10.0, 3.0 Hz) and δC 91.7 and for sulfoxide syn-rac-103 were

δH 5.72 (doublet of doublets, J = 9.5, 4.0 Hz) and δC 86.8. Each diastereoisomer was

shown to be separable into a 50:50 mixture of enantiomers by CSP-HPLC. Assignment

of the relative stereochemistry is provided later (see Scheme 2.24).

OCbPh

1. s-BuLi, TMEDA

Et2O, _78 °C, 1 h

2.

anti-rac-103, 25% syn-rac-103, 32%14

Cb = CONiPr2

SOMe

O

121

SPh

CbO H

O

SPh

CbO H

O

Scheme 2.11

Next, the use of Andersen’s sulfinate (SS)-97 as the electrophile was explored.

Andersen’s sulfinate (SS)-97 was synthesised using a modified Solladié procedure.120

First, sodium p-toluene sulfinate was treated with thionyl chloride to give sulfinyl

chloride 122 (Scheme 2.12). Then, after removal of excess thionyl chloride by

distillation, (−)-menthol was added to give a single diastereoisomer of Andersen’s

sulfinate (SS)-97 in 50% yield after recrystallisation.


44

SO

O

(SS)-97, 50%

SONa

O

SCl

O

122

SOCl2

PhMe, rt, 2 h

1. (_)-menthol, pyridine

Et2O, rt, 16 h

2. Recrystallisation

Scheme 2.12

Due to extensive literature precedence,110,112,113,121,122

it was anticipated that addition of

the lithiated intermediate to Andersen’s sulfinate (SS)-97 would proceed with complete

inversion of configuration at sulfur, leading to the isolation of two enantiopure

diastereomeric sulfoxides. However, this was not the case. Lithiation of O-alkyl

carbamate 14 with s-BuLi/TMEDA and trapping with Andersen’s sulfinate (SS)-97 gave

diastereomeric sulfoxides anti-(S,Ss)-103 (25%) and syn-(R,Ss)-103 (21%) in 87:13 er

and 85:15 er respectively (Scheme 2.13). The enantiomeric ratios were determined by

CSP-HPLC and were much lower than expected.

OCbPh

1. s-BuLi, TMEDA,

Et2O, _78 °C, 1 h

2.

14S

O

O

(SS)-97

ant i-(S,Ss)-103

25%, 87:13 ersyn-(R,Ss)-103

21%, 85:15 erCb = CONiPr2

SPh

CbO H

O

SPh

CbO H

O

Scheme 2.13

It was postulated that the lack of stereospecificity in the trapping reaction could be due

to the electrophilicity of the sulfoxide products that are formed. This could cause a

sulfoxide → lithium exchange to occur during the trapping procedure. Our proposed

mechanistic scenario is shown in Scheme 2.14. The reaction begins with a racemic

lithiation of carbamate 14 to give a 50:50 ratio of enantiomeric lithiated adducts (S)-26

and (R)-26. Subsequent trapping with Andersen’s sulfinate (SS)-97 would then give

sulfoxides anti-(S,SS)-103 and syn-(R,SS)-103. The trapping process is presumed to

occur with inversion of configuration at sulfur in line with the literature precedent.113

However, due to the stability of (S)-26 and (R)-26, it is possible for a nucleophilic

addition to the sulfoxide products to occur. This would expel organolithium reagents


45

(S)-26 or (R)-26 as a leaving group. In a similar fashion, the addition to the sulfoxide is

presumed to occur with inversion of configuration at sulfur resulting in sulfoxides syn-

(S,RS)-103 and anti-(R,RS)-103 being formed. These sulfoxides are the enantiomers of

those formed in the initial trapping reaction. This mechanism would explain the

reduction in enantiomeric ratio observed in the major products anti-(S,SS)-103 and syn-

(R,SS)-103.

OCbPhs-BuLi, TMEDA

SPh

O

SPh

OCb

O

14

SO

O

(SS)-97

OCb


LiPh

(S)-26

LiPh

(R)-26

OCb OCb

SPh

O

SPh

OCb

O

OCb

LiPh LiPh

OCb OCb

syn-(S,Rs)-103 ant i-(R,Rs)-103

Et2O, _78 °C, 3 h

(S)-26 (R)-26

Cb = CONiPr2

(SS)-97 (SS)-97

50:50

Scheme 2.14

To probe this mechanism, a crossover experiment was designed. This experiment

would introduce an alternative lithiated O-alkyl carbamate into the presence of the

sulfoxide products formed by lithiation-trapping of O-alkyl carbamate 14. Our choice

was to add lithiated O-ethyl carbamate 28 to sulfoxide anti-rac-103 at −78 °C (Scheme

2.15). If ethyl sulfoxides anti-rac-123 and syn-rac-123 were isolated from this reaction

then it would prove that a sulfoxide → lithium exchange reaction occurs between

lithiated O-alkyl carbamates and the sulfoxide formed during the lithiation-trapping

reaction.


46

Li

28Cb = CONiPr2

ant i-rac-123 syn-rac-123

S

CbO H

O

ant i-rac-103

SPh

CbO H

O

S

CbO H

O

_78 °C, 1 h

OCb

Scheme 2.15

Before carrying out the crossover experiment, ethyl sulfoxides anti-rac-123 and syn-

rac-123 were independently synthesised by lithiation of O-ethyl carbamate 124

(synthesised from ethyl chloroformate and diisopropyl amine as reported in the

literature)123

using s-BuLi/TMEDA at −78 °C for 1 hour and trapping with methyl p-

toluene sulfinate 121 (Scheme 2.16). Sulfoxides anti-rac-123 and syn-rac-123 were

isolated in 29% and 22% yield respectively. The OCH signals provided key diagnostic

information for sulfoxide anti-rac-123 (δH 5.52, quartet, J = 6.5 Hz and δC 89.3) and for

sulfoxide syn-rac-123 (δH 5.80, quartet, J = 6.5 Hz and δC 84.0). Assignment of the

relative stereochemistry is provided later (see Scheme 2.25).

OCb

1. s-BuLi, TMEDA

Et2O, _78 °C, 1 h

2.

124Cb = CONiPr2

ant i-rac-123, 29% syn-rac-123, 22%

S

CbO H

O

S

CbO H

OS

O

OMe

121

Scheme 2.16

For the crossover experiment, O-ethyl carbamate 124 was lithiated by s-BuLi/TMEDA

and then sulfoxide anti-rac-103 was added. After stirring the reaction for 1 hour at −78

°C, the reaction was quenched with methanol. Purification by flash column

chromatography gave a mixture of four inseparable sulfoxides. Analysis of the 1H

NMR spectrum of the sulfoxide mixture allowed the determination of yield based on

sulfoxide anti-rac-103. Recovered anti-rac-103 was isolated in 66% yield and its

epimer, sulfoxide syn-rac-103, was formed in 5% yield. It is postulated that syn-rac-

103 could be formed by either a double substitution event or α-deprotonation of anti-

rac-103. Crucially, ethyl carbamate sulfoxides anti-rac-123 and syn-rac-123 were

formed in 13% and 12% yield respectively (Scheme 2.17).


47

OCb

1. s-BuLi, TMEDA

Et2O, _78 °C, 1 h

2.

ant i-rac-103, 66% syn-rac-103, 5%124

Cb = CONiPr2

ant i-rac-123, 13% syn-rac-123, 12%

S

CbO H

O

ant i-rac-103

SPh

CbO H

O

SPh

CbO H

O

SPh

CbO H

O

S

CbO H

O

Scheme 2.17

This experiment shows that during the lithiation-trapping reaction, it is possible for

excess lithiated intermediate to attack the forming sulfoxides. This would cause a

second inversion of configuration at sulfur to take place. Hence, sulfoxides anti-(S,SS)-

103 and syn-(R,SS)-103 could be formed in reduced enantiomeric ratio.

Closer inspection of the literature revealed a number of isolated examples of low

stereochemical fidelity during the reaction of organolithium reagents with enantiopure

sulfinates.124-126

One example is shown in Scheme 2.18. Kagan and co-workers

reported that the lithiation of ferrocene and trapping with Andersen’s sulfinate (SS)-97

gave sulfoxide (SS)-125 in 69% yield but only 91:9 er.

Fe3.

Fe

(SS)-125

69%, 91:9 er

S

pTol

O

SO

O

(SS)-97

1. t-BuOK, THF, _78 °C, 30 min

2. t-BuLi, _78 to _25 °C , 30 min

Scheme 2.18

We suggest that the loss of enantiomeric ratio of sulfoxide (SS)-125 could be explained

using the mechanism outlined in Scheme 2.14. In this case, lithiated ferrocene would

attack sulfoxide (SS)-125 as it forms, with inversion of configuration at sulfur giving


48

some of the enantiomeric sulfoxide (RS)-125. The key to the lack of stereospecificity is

having a moderately stabilised organolithium that can act as a leaving group.

With the mechanism for loss of enantiomeric ratio identified, a series of experiments

were carried out in order to improve the enantioselectivity of the lithiation-trapping.

The results are shown in Scheme 2.19 and Table 2.1 and the initial result from Scheme

2.13 is shown in entry 1. First, we hypothesised that the process of warming the

reaction from −78 °C to room temperature over 16 hours was the cause of the lower

enantiomeric ratio. Since we had already shown that sulfoxide → lithium exchange

took place within 1 hour at −78 °C, we chose to quench the reaction 5 minutes after

Andersen’s sulfinate (SS)-97 was added. This allowed us to isolate sulfoxides anti-

(S,SS)-103 and syn-(R,SS)-103 in a significantly improved 88:12 er and 91:9 er

respectively (entry 2).

The mechanism we proposed for the loss of enantiomeric ratio requires a second

addition of nucleophile to the sulfoxide products in order to invert the configuration at

sulfur. Therefore, when there is an excess of lithiated intermediates (R)-26 and (S)-26,

this inversion event is favoured. We postulated that by using a reverse addition

protocol, whereby the lithiated intermediates are added to Andersen’s sulfinate (SS)-97

via cannula transfer, there would never be an excess of nucleophile present within the

reaction mixture. Using the reverse addition protocol did not significantly enhance the

enantioselectivity as sulfoxides anti-(S,SS)-103 and syn-(R,SS)-103 were isolated in

87:13 er and 90:10 er respectively (entry 3).

OCbPh

1. s-BuLi, TMEDA,

Et2O, _78 °C, 1 h

2. X eq. Andersen's

Sulfinate (Ss)-97

SPh

O

SPh

CbO H

O

14

SO

O

(Ss)-97

H OCb


Cb = CONiPr2

Scheme 2.19


49

Table 2.1: Optimisation of the Racemic Lithiation of O-Alkyl Carbamate 14 and

Trapping with Andersen’s sulfinate (SS)-97

Entry X Reverse

Addition

Trap Length

/ min


Yield / % era Yield / % er

a

1 1.3 No 16 h b 25 83:17 21 85:15

2 1.3 No 5 23 88:12 32 91:9

3 1.3 Yes 5 25 87:13 29 90:10

4 2.0 Yes 5 21 92:8 24 95:5

5 3.0 Yes 5 26 90:10 31 93:7

6c 1.3 No 30 8 92:8 8 87:13

aer determined by CSP-HPLC,

b Warmed from −78 °C to room temperature,

c

Transmetallation with MgBr2 before addition of Andersen’s sulfinate (SS)-97

The enantioselectivity was further improved by using 2.0 eq. of Andersen’s sulfinate

(SS)-97 (entry 4) whereas use of 3.0 eq. of Andersen’s sulfinate (SS)-97 did not lead to

further improvement (entry 5). Finally, we attempted to transmetalate the lithiated

intermediates by treatment with MgBr2 (entry 6).74

It was hypothesised that the

nucleophilicity of the organometallic reagent could be influenced leading to a reduced

propensity for addition to the sulfoxide product. Unfortunately, this led to a poor

overall yield (16%) but there was a modest improvement in the enantioselectivity in

both diastereomeric sulfoxides anti-(S,SS)-103 (92:8 er) and syn-(R,SS)-103 (87:13 er)

compared to an analogous organolithium reaction (entry 1).

To conclude, our optimised conditions for the trapping of lithiated O-alkyl carbamates

was using 2.0 eq. Andersen’s sulfinate (SS)-97 and a reverse addition protocol (addition

of lithiated carbamate to Andersen’s sulfinate (SS)-97). This gave sulfoxides anti-

(S,SS)-103 and syn-(R,SS)-103 in 92:8 er and 95:5 er respectively. However, we were

unable to generate products in ≥99:1 er using the racemic lithiation method.


50

2.2.2 s-BuLi/Chiral Ligand-mediated Lithiation of O-Alkyl Carbamates and

Trapping with Andersen’s Sulfinate

To overcome our inability to isolate the α-alkoxy sulfoxides in ≥99:1 er, our thoughts

then turned to a chiral amplification strategy. It was postulated that an asymmetric

lithiation of O-alkyl carbamate 14 mediated by s-BuLi/chiral diamine and subsequent

trapping with Andersen’s sulfinate (SS)-97 would lead to an increase in

enantioselectivity in the major sulfoxide diastereoisomer (and a simultaneous loss of

enantiomeric ratio in the minor diastereoisomer) due to two chiral partners reacting with

one another. Furthermore, we would expect the enantiomeric ratio for the major

diastereoisomer to be (v × y):(w × z), where v:w is the enantiomeric ratio of the first

enantioselective reaction and y:z is the enantiomeric ratio of the second.32

As an example, s-BuLi/(+)-sparteine surrogate 1 is reported in the literature to give 93:7

er127

in the asymmetric lithiation of O-alkyl carbamate 14 and we have shown that,

using the reverse addition protocol, Andersen’s sulfinate (SS)-97 traps with ca. 90:10

er. Therefore, the enantiomeric ratio of the major diastereoisomer, sulfoxide syn-(R,SS)-

103, should be (93×90):(7×10) = (8370):(70) = >99:1 er (Scheme 2.20). The increase in

the enantiomeric ratio observed in the major diastereoisomer will be at the expense of

the enantiomeric ratio of the minor diastereoisomer which will be reduced.

OCbPhs-BuLi, (+)-sp. surr. 1

Andersen's

Sulfinate (SS)-97

SPh

O

SPh

CbO H

O

14

SO

O

(SS)-97 CbO H

anti-(S,Ss)-103syn-(R,Ss)-103

Ph Ph

CbO HCbO H

Li

(R)-26

Li

(S)-26Et2O, _78 °C, 3 h

ca. 93:7

ca. 90:10ca.90:10

(93 x 90):(7 x 10)= 8370:70 = 99:1 er

(93 x 10):(90 x 7)= 930:630 = 60:40 er

N

NH


Scheme 2.20


51

With this in mind, it is essential to first know the enantioselectivity obtained with

different ligands in the lithiation-trapping of O-alkyl carbamate 14. The investigation

would involve the use of (−)-sparteine, (+)-sparteine surrogate 1 and diamine (S,S)-42.

Previously, our group has reported that lithiation of O-alkyl carbamate 14 with s-

BuLi/(−)-sparteine and trapping with methyl chloroformate gave ester (R)-126 in 84%

yield and 97:3 er. In addition, lithiation with s-BuLi/(+)-sparteine surrogate 1 gave

ester (S)-126 in 67% yield and 93:7 er (Scheme 2.21). It is also worth noting that

lithiation of O-alkyl carbamate 14 with s-BuLi/(−)-sparteine has been reported to give

trapped products in 99:1 er in some cases.128

OCbPh

1. s-BuLi, Ligand

Et2O, _78 °C, 1 h

2. MeOCOClPh

14

H OCb

O

OMe

(R)-126

N

NH

H N

NH

(_)-Sparteine (+)-SparteineSurrogate 1Cb = CONiPr2

84%, 97:3 er 67%, 7:93 er

Scheme 2.21

Alexakis introduced diamine 42 as a ligand to direct organolithium addition to

imines.129

It is readily available as either enantiomer and has been used in our group as

a (+)-sparteine surrogate.29

It is of particular interest due to the current global shortage

of (−)-sparteine and only one enantiomer of (+)-sparteine surrogate 1 being readily

available. In our hands, lithiation of O-alkyl carbamate 14 mediated by s-BuLi/(S,S)-42

and trapping with cyclohexanone gave alcohol (R)-127 in 72% yield and 82:18 er

(Scheme 2.22).

NMe

MeN

tBu

tBu

(S,S)-42

OCbPh

1. s-BuLi, (S,S)-42

Et2O, _78 °C, 1 h

2. CyclohexanonePh

14

CbO H

Cb = CONiPr2

HO

(R)-12772%, 82:18 er

Scheme 2.22

With knowledge of the inherent enantioselectivity of the different chiral diamines, we

were now in a position to undertake the asymmetric lithiation of O-alkyl carbamate 14

and trapping with Andersen’s sulfinate (SS)-97. To our delight, lithiation mediated by s-


52

BuLi/(−)-sparteine gave anti-(S,SS)-103 in 53% yield and 99:1 er (Scheme 2.23, Table

2.2, entry 1). Diastereomeric sulfoxide syn-(R,SS)-103 was isolated in only 0.2% yield

(enantiomeric ratio not determined). The opposite diastereoisomer was also synthesised

as the major product by changing the ligand to the (+)-sparteine surrogate 1. Lithiation

of O-alkyl carbamate 14 with s-BuLi/(+)-sparteine surrogate 1 and trapping with

Andersen’s sulfinate (SS)-97 gave sulfoxide anti-(S,SS)-103 in 7% yield and 87:13 er

and sulfoxide syn-(R,SS)-103 in 54% yield and 99:1 er (entry 2). Thus, either

diastereoisomer of α-alkoxy sulfoxides was accessible in 99:1 er.

OCbPh

1. s-BuLi, Ligand

Et2O, _78 °C, 3 h

2.

14 SO

O

(SS)-97

anti-(S,Ss)-103 syn-(R,Ss)-103Cb = CONiPr2

SPh

CbO H

O

SPh

CbO H

O

Scheme 2.23

Table 2.2: Asymmetric Lithiation of O-Alkyl Carbamate 14 and trapping with

Andersen’s Sulfinate (SS)-97

Entry Ligand anti-(S,SS)-103 syn-(R,SS)-103


a

1 (−)-sparteine 53 99:1 0.2 nd

2 (+)-sparteine surrogate 1 7 87:13 45 99:1

3 (S,S)-42 17 95:5 54 99:1

4 (R,R)-42 56 99:1 14 93:7

aer determined by CSP-HPLC, nd = not determined

Furthermore, the lithiation using diamine (S,S)-42 as the ligand gave sulfoxide anti-

(S,SS)-42 in 17% yield and 95:5 er and sulfoxide syn-(R,SS)-103 in good yield (54%)

and excellent enantiomeric ratio (99:1 er) (entry 3). Finally, lithiation mediated by s-

BuLi/diamine (R,R)-42 gave sulfoxide anti-(S,SS)-103 in 56% yield and 99:1 er and

sulfoxide syn-(R,SS)-103 in 14% yield and 93:7 er (entry 4). Crucially, we can


53

synthesise either diastereoisomer in 99:1 er without the need to use (−)-sparteine or (+)-

sparteine surrogate 1.

The successful asymmetric lithiation protocols also allowed us to assign the

stereochemistry of the diastereomeric sulfoxides (Scheme 2.24). It is well established

that the lithiation of O-alkyl carbamate 14 with s-BuLi/(−)-sparteine gives lithiated

intermediate (S)-26 in high enantiomeric ratio (ca. 97:3 er).21

Trapping of (S)-26 with

Andersen’s sulfinate (SS)-97 occurs with inversion of configuration at sulfur.113

Therefore, it was expected that sulfoxide anti-(S,SS)-103 would be the major

diastereomer in this case. On the other hand, lithiation of O-alkyl carbamate 14

mediated by s-BuLi/(+)-sparteine surrogate 1 is known to give (R)-26 in 93:7 er.127

Subsequent trapping of the lithiated intermediate with Andersen’s sulfinate (SS)-97

would lead to the formation of syn-(R,SS)-103 as the major diastereoisomer.

OCbPhs-BuLi, (_)-sparteine

Andersen's

Sulfinate (SS)-97

SPh

O

SPh

CbO H

O

14

SO

O

(SS)-97

H OCb


Ph Ph

CbO HH OCb

Li

(S)-26

Li

(R)-26

OCbPhs-BuLi, (+)-sp. surr. 1

14

Ph Ph

CbO HH OCb

Li

(S)-26

Li

(R)-26

Et2O, _78 °C, 3 h

Et2O, _78 °C, 3 h

ca. 97:3

ca. 7:93

Andersen's

Sulfinate (SS)-97

'major '

'major ''minor'

'minor'

Scheme 2.24

In a similar fashion, the relative stereochemistry of the O-ethyl sulfoxides was assigned.

Lithiation of O-ethyl carbamate 124 mediated by s-BuLi/(S,S)-42 and trapping with


54

Andersen’s sulfinate (SS)-97 gave sulfoxides anti-(S,Ss)-123 and syn-(R,Ss)-123 in 4%

and 9% yield respectively (Scheme 2.25). We were unable to determine the

enantiomeric ratios by CSP-HPLC. Importantly, the relative stereochemistry can be

assigned from the known29,32

induction of diamine (S,S)-42 and trapping of Andersen’s

sulfinate with inversion of configuration at sulfur to give syn-(R,SS)-123 as the major

diastereomeric sulfoxide.

OCb

1. s-BuLi, (S,S)-42

Et2O, _78 °C, 1 h

2.

124

Cb = CONiPr2

anti-(S,SS)-123, 4% syn-(R,SS)-123, 9%

S

CbO H

O

S

CbO H

O

SO

O

(SS)-97

Scheme 2.25

To conclude, by combining highly enantioselective lithiation reactions and trapping

with Andersen’s sulfinate (SS)-97, it is possible to synthesis either diastereoisomer of

sulfoxides anti-(S,SS)-103 and syn-(R,SS)-103 in 45-54% yield and 99:1 er.


55

2.3 Sulfoxide → Magnesium Exchange of α-Alkoxy Sulfoxides

With a robust method for the synthesis of sulfoxides anti-(S,SS)-103 and syn-(R,SS)-103

in hand, we set about using them to create α-alkoxy Grignard reagents in 99:1 er. The

method of choice was sulfoxide → magnesium exchange, due to significant precedent

for high stereochemical fidelity during the reaction (see Scheme 1.41).90,91

In addition,

we were expecting that the α-alkoxy Grignard reagents would have a higher degree of

configurational stability when compared to their organolithium counterparts.72

However, there is no precedent for carrying out sulfoxide magnesium → exchange

reactions at higher temperatures, such as 0 °C or above. This was one of our key aims.

2.3.1 Optimising the Sulfoxide → Magnesium Exchange Reaction

It was hypothesised that the sulfoxide → magnesium exchange reaction would occur

very quickly at temperatures ≥0 °C. Therefore, racemic sulfoxide anti-rac-103 was

treated with 1.1 eq. of i-PrMgCl in THF at 0 °C, and methyl chloroformate was added

after just 10 seconds (Scheme 2.26, Table 2.3). This led to ester rac-126 being isolated

in 49% yield (entry 1). In addition, sulfoxide rac-128 (formed as a by-product of the

sulfoxide → magnesium exchange product whereby i-PrMgCl attacks at the sulfur

atom) was isolated in 54% yield and starting sulfoxide anti-rac-103 was recovered in

20% yield. With a significant amount of starting material being recovered, the number

of equivalents of Grignard reagent and the reaction time were increased. Treatment of

sulfoxide anti-rac-103 with 1.3 eq. i-PrMgCl for 1 minute at 0 °C and trapping with

methyl chloroformate gave ester rac-126 in an improved 58% yield and a reduction in

recovered sulfoxide anti-rac-103 (3%) (entry 2). However, sulfoxide rac-128 was

isolated in 74% yield, indicating that the exchange reaction had occurred to a much

larger degree than previously. Furthermore, carbamate 14 was isolated in 3% yield.

Carbamate 14 was presumably formed by the Grignard reagent from the initial

exchange reaction being quenched with a proton which could come from the α-proton in

sulfoxide rac-128 which is formed as the by-product from the sulfoxide → magnesium

exchange reaction.


56

1. n eq. i-PrMgCl, THFTemp., Time

2. n eq. MeOCOClSPh

O

CbO H

anti-rac-103

PhOMe

O

rac-126

Ph OCb

14

SpTol

O

rac-128

OCb

Cb = CONiPr2

Scheme 2.26

Table 2.3: Optimisation of the Sulfoxide → Magnesium Exchange of anti-rac-103

Entry n Temp.

/ °C

Time

/ min

Yield rac-

126 / %

Yield 14

/ %

Yield rac-

128 / %

Recovered

anti-103 / %

1 1.1 0 10 s 49 - 54 20

2 1.3 0 1 58 3 74 3

3 1.3 rt 20 s 56 1 71 5

4 1.3 rt 1 65 6 73 8

5 1.3 rt 5 48 14 81 4

6 1.5 rt 1 67 9 84 0

7 1.5 rt 5 42 17 82 0

8 2.5 rt 1 75 5 84 0

The yield of ester rac-126 was further improved to 65% by carrying out the reaction at

room temperature for 1 minute using 1.3 eq. of i-PrMgCl but the yield of carbamate 14

was also increased (6%) (entry 4). Repeating the reaction under the same conditions but

reducing the time to 20 seconds led to ester rac-126 being isolated in a reduced 56%

yield (entry 3). Extension of the reaction time to 5 minutes gave ester rac-126 in a poor

48% yield but sulfoxide rac-128 was isolated in an improved 81% yield (entry 5). This

suggests that the initial exchange reaction is high yielding but the intermediate Grignard

reagent has more time to be protonated. An increased yield of carbamate 14 also

supports this notion. Under each of these reaction conditions there was still a small

amount of starting sulfoxide anti-rac-103 recovered (4-8%).

Therefore, we decided to increase the number of equivalents of i-PrMgCl. Addition of

1.5 eq. of i-PrMgCl to sulfoxide anti-rac-103 at room temperature for 1 minute gave

ester rac-126 in 67% yield and sulfoxide rac-128 in 84% (entry 6). In addition,

carbamate 14 was isolated in 9% yield indicating a small amount of protonation

occurred under the reaction conditions. Extending the reaction to 5 minutes saw a


57

reduction in yield of ester rac-126 (42%) but an increase in yield of carbamate 14 (17%)

(entry 7). Finally, it was hypothesised that having a large excess of i-PrMgCl present

within the reaction would lead to a reduction in the protonation of the Grignard

intermediate. Indeed, using 2.5 eq. i-PrMgCl reduced the yield of carbamate 14 to 5%

whilst increasing the yield of ester rac-126 (75%) (entry 8). We postulate that the

excess i-PrMgCl may deprotonate sulfoxide rac-128 whilst it is being formed.

However, deuteriation experiments proved inconclusive.

In an attempt to form a sulfoxide by-product without an α-proton, exchange reactions

were carried using t-BuMgCl and PhMgCl (Scheme 2.27). Unfortunately, neither of

these Grignard reagents facilitated sulfoxide → magnesium exchange. Instead starting

sulfoxide anti-rac-103 was recovered unchanged in each case.

1. t-BuMgCl or PhMgClTHF, rt,1 min

2. MeOCOClSPh

O

CbO H

anti-rac-103

PhOMe

O

rac-126

OCb

Cb = CONiPr2 Not Formed

Scheme 2.27

The optimised conditions for the synthesis of α-alkoxy Grignard reagents by sulfoxide

→ magnesium exchange were found to be 2.5 eq. of i-PrMgCl at room temperature for

1 min (Table 2.3, entry 8). However, the 75% yield of ester rac-126 is slightly

disappointing given the high 84% yield of sulfoxide rac-128 that was also isolated.

Finally, diastereomeric sulfoxide syn-rac-103 was shown to give comparable reactivity

under the optimised conditions (Scheme 2.28). Indeed, ester rac-126 was isolated in

67% yield and sulfoxide rac-128 in 79% yield. Furthermore, we isolated carbamate 14

in 7% yield indicating that protonation of the intermediate Grignard reagent occurred to

a similar extent as previously observed.


58

1. 2.5 eq. i-PrMgCl,THF, rt, 1 min

2. 2.5 eq. MeOCOClSPh

O

CbO H

syn-rac-103

PhOMe

O

rac-126, 67%

Ph OCb

14, 7%

SpTol

O

rac-128, 79%

OCb

Cb = CONiPr2

Scheme 2.28

2.3.2 Synthesis and Reactions of Enantiopure α-Alkoxy Grignard Reagents

Next, we wanted to undertake a sulfoxide → magnesium exchange on sulfoxides anti-

(S,SS)-103 and syn-(R,SS)-103 of 99:1 er. In addition to synthesising a wide range of

products in 99:1 er, this would also allow us to investigate the configurational stability

of α-alkoxy Grignard reagents at room temperature.

Sulfoxide anti-(S,SS)-103 was treated with 2.5 eq. i-PrMgCl at room temperature for 1

minute and then methyl chloroformate was added (Scheme 2.29). To our delight, ester

(R)-126 was isolated in 73% yield and 99:1 er. Comparison to the literature data for

ester (R)-126127

allows us to conclude that sulfoxide → magnesium exchange and

trapping proceeds with retention of configuration at carbon. Grignard reagent (S)-104

was also trapped with allyl bromide (with 10 mol% CuBr.SMe2 as a catalyst) and

cyclohexanone which gave alkene (R)-129 and alcohol (R)-127 in good yields and

excellent enantioselectivity. All three racemic compounds were prepared in a similar

way from anti-rac-103 and separated by CSP-HPLC.

Ph E

HCbO

SPh

O

CbO H

anti-(S,SS)-103, 99:1 er

MgClPh

CbO H

THF, rt, 1 min

i-PrMgCl E+

(S)-104

PhOMe

O

HCbO

(R)-126

73%, 99:1 er

E+= MeOCOCl

Ph

HCbO

(R)-129

70%, 99:1 er

E+= allyl-Br

(10 mol% CuBr.SMe2)

(R)-127

71%, 99:1 er

E+= cyclohexanone

Ph

CbO H

HO

Scheme 2.29


59

Reaction of Grignard reagent (S)-104 with aldehydes was also explored (Scheme 2.30).

Grignard reagent (S)-104 was synthesised from sulfoxide (S,SS)-103 and subsequent

addition of aldehydes gave mono-protected diols (R,S)-130-133 with anti-

diastereoselectivity (70:30 to ≥99:1 dr, inseparable mixtures) in 65-78% yields with

each diastereoisomer being formed in 99:1 er.

PhR

OH

HCbO

PhPh

OH

HCbO

PhtBu

OH

HCbO

PhiPr

OH

HCbO

PhnBu

OH

HCbO

(R,S)-130, 99:1 er71%, 90:10 dr

PhCHO

(R,S)-131, 99:1 er78%, 70:30 dr

t-BuCHO

(R,S)-132, 99:1 er70%, 99:1 dr

i-PrCHO

(R,S)-133, 99:1 er65%, 90:10 dr

n-BuCHO

SPh

O

CbO H

anti-(S,SS)-103, 99:1 er

MgClPh

CbO H

THF, rt, 1 min

i-PrMgCl RCHO

(S)-104

Scheme 2.30

Reduction of (R,S)-133 using LiAlH4 gave known130

diol (R,S)-134 in 89% yield

(Scheme 2.31). Comparison of the 1H NMR and

13C NMR spectra allowed assignment

of the relative stereochemical configuration. Alcohols (R,S)-130-133 were assigned by

analogy.

PhnBu

OH

HCbO

(R,S)-133, 99:1 er90:10 dr

THF, reflux, 1 h

LiAlH4

PhnBu

OH

HHO

(R,S)-134, 89%90:10 dr

Scheme 2.31

Sulfoxide → magnesium exchange and trapping with aldehydes offers an attractive

connective strategy for the synthesis of anti-1,2-diols which are typically synthesised in

two steps by Wittig reaction and asymmetric dihydroxylation. A related approach was

recently reported by Shen and co-workers starting from TsCH2OCb and aldehydes.131

The opposite enantiomer of all the products would be equally accessible from sulfoxide

(R,SS)-103. To demonstrate this, treatment of sulfoxide syn-(R,SS)-103 with i-PrMgCl


60

gave Grignard reagent (R)-104 and trapping with cyclohexanone gave alcohol (S)-127

in 74% yield and 99:1 er (Scheme 2.32).

S

O

SPh

O

CbO H

syn-(R,SS)-103, 99:1 er

MgClPh

CbO H

THF, rt1 min

i-PrMgCl

(R)-104

Ph

CbO H

HO

(S)-127, 74%99:1 er

O

(SS)-128, 78%

Scheme 2.32

Moreover, sulfoxide (SS)-128 was isolated in 78% yield from this reaction. Comparison

of the optical rotation with that reported in the literature confirms the absolute

configuration of sulfoxide (SS)-128; our synthesised (SS)-128 had [α]D −194.2 (c 1.0 in

EtOH) and the literature value was [α]D −187 (c 2.4 in EtOH).115

Sulfoxide (SS)-128 is

the expected product of double inversion from Andersen’s sulfinate (SS)-97 and allows

confirmation of the assignment of the configuration in sulfoxides anti-(S,SS)-103 and

syn-(R,SS)-103

The major limitation with the use of O-alkyl carbamate 14 is that a carbamate

deprotection is required to furnish the synthetically desirable secondary alcohols.

However, boronate rearrangements, as reported initially by Hoppe30,33

and later

developed by Aggarwal,32

allow direct access to the alcohol (see Schemes 1.8 and 1.9).

Hence, we were interested in exploring this chemistry via our methodology. Therefore,

i-PrMgCl was added to sulfoxide anti-(S,SS)-103 followed by trapping with i-BuB-

pinacolate. After refluxing for 16 hours, subsequent oxidation (H2O2, NaOH) gave

alcohol (R)-135 in 68% yield but only 94:6 er (Scheme 2.33).

2. H2O2, NaOH

rt, 2 h

SPh

O

CbO H

anti-(S,SS)-103, 99:1 er

Ph

HO

(R)-13568%, 94:6 er

MgClPh

CbO H

THF, rt, 1 min

i-PrMgCl1. i-BuB(pin),

reflux, 16 h

(S)-104

H

Scheme 2.33

The loss of enantiomeric ratio in the metallate rearrangement with magnesium has been

previously observed by Blakemore and co-workers (and later commented on by


61

Aggarwal).32,92,121

Indeed, reaction of Grignard reagent (S)-81, generated by sulfoxide

→ magnesium exchange from (R,RS)-80, with Ph(CH2)2B-dioxaborinane and

subsequent oxidation (H2O2, NaOH) gave alcohol (S)-84 in 49% yield but only 91:9 er

(Scheme 2.34). Alternatively, use of organolithium (S)-136 (formed by sulfoxide →

lithium exchange) allowed access to alcohol (S)-84 in a much improved 98:2 er. No

further explanation for this increase in stereochemical fidelity was offered.

S

O

Cl

Ph Ph

ClMg

Cl

PhMe_78 °C, 30 min

EtMgCl Ph

OH

Ph

O

B

OPh

2. H2O2, NaOH

EtOH-THF, 0 °C

1.

S

O

Cl

Ph Ph

Li

Cl

THF_78 °C, 30 min

n-BuLi Ph

OH

Ph

O

B

OPh

2. H2O2, NaOH

EtOH-THF, 0 °C

1.

(S)-84, 49%91:9 er

(S)-84, 70%98:2 er

(R,RS)-80, 99:1 er

(R,RS)-80, 99:1 er

(S)-81

(S)-136

Scheme 2.34

We too turned to organolithium reagents to solve the loss of configuration within the

1,2-metallate rearrangement. To our delight, sulfoxide → lithium exchange of anti-

(S,SS)-103 using n-BuLi (THF, −78 °C, 1 min) and reaction with i-BuB-pinacolate

followed by oxidation with H2O2 and NaOH gave alcohol (R)-135 in 72% yield and

99:1 er (Scheme 2.35).

2. H2O2, NaOHrt, 2 h

SPh

O

CbO H

anti-(S,SS)-103

Ph

HO

(R)-13572%, 99:1 er

LiPh

CbO H

_78 °C, 1 min

n-BuLi, THF1. i-BuB(pin),

reflux, 16 h

H

(S)-26

Scheme 2.35

Finally, we investigated the configurational stability of Grignard reagent (S)-104 at

room temperature over longer times than 1 minute. Extended sulfoxide → magnesium

exchange reaction times of 15 and 30 minutes and trapping with cyclohexanone gave

alcohol (R)-127 in 98:2 er in both cases (Scheme 2.36). It is believed that reduced

yields (34% and 24% yield respectively) with extended sulfoxide → magnesium


62

exchange times are due to protonation of Grignard reagent (S)-104 by the sulfoxide by-

product as previously discussed. Furthermore, no evidence of 1,2-carbamoyl migration

was observed (this process is reported to take place in corresponding organolithium

reagents at −20 °C)73

. From this marginal loss of enantiomeric ratio in the products

(within the error limits of HPLC detection), it is concluded that Grignard reagent (S)-

104 is configurationally table at room temperature for 30 minutes. This is consistent

with observations made by Nakai and co-workers.72

SPh

O

CbO H

anti-(S,SS)-103, 99:1 er

MgClPh

CbO H

THF, rt,1-30 min

i-PrMgCl

(S)-104

Ph

CbO H

HO

(R)-127

Exchange Time1 min: 71%, 99:1 er

15 min: 34%, 98:2 er30 min: 24%, 98:2 er

O

Scheme 2.36

To conclude, we can access α-substituted O-alkyl carbamates via our lithiation-trapping

and subsequent sulfoxide → magnesium exchange methodology. For example, ester

(R)-126 was isolated in 41% yield and 99:1 er over two steps from O-alkyl carbamate

14 (Scheme 2.37). Importantly, this reaction sequence does not require the use of (−)-

sparteine and the divergent electrophilic trapping step can be carried out at room

temperature over short reaction times. Significantly, α-alkoxy Grignard reagents have

been shown to be configurationally stable at room temperature for up to 30 minutes.

SPh

O

CbO H

ant i-(S,SS)-103

56%, 99:1 er

Ph

CbO H

(R)-126, 73%

OMe

O

Ph OCb

1. s-BuLi, (R,R)-42

Et2O, _78 °C, 1 h

2.

14

Cb = CONiPr2S

O

O

(SS)-97

41% over two steps99:1 er

2. MeOCOCl

1. i-PrMgCl, THFrt, 1 min

Scheme 2.37


63

2.4 Synthesis of Tertiary Alcohols from Sulfoxides via Sulfoxide →

Magnesium Exchange

In 2008, Aggarwal et al. reported the enantioselective synthesis of tertiary alcohols (e.g.

(R)-137) from secondary benzylic O-alkyl carbamates (e.g. (S)-9) using lithiation-

boronate rearrangement methodology (Scheme 2.38).34

This chemistry was reviewed in

detail in Chapter 1.1.1. The requirement of the phenyl substituent to lower the pKa of

the α-proton for the deprotonation reaction is a still a major limitation as the phenyl

substituent then remains in the product.

Ph

OCb

Ph

Et OH1. s-BuLi, Et2O, _78 °C, 20 min

2. EtB(pin),

3. H2O2,NaOH(S)-999:1 e.r

(R)-13795%, 99:1 er

Scheme 2.38

It was proposed that sulfoxide → magnesium exchange methodology could offer an

improvement in the synthesis of tertiary alcohols by allowing access to products lacking

an aryl substituent (Scheme 2.39). Our plan would be two-fold. First, the synthesis of

quaternary α-alkoxy sulfoxides anti-(S,SS)-138 by alkylation of anti-(S,SS)-103 would

be explored. Second, sulfoxide → magnesium exchange to give (S)-139 and subsequent

boronate rearrangement would allow access to a wide range of chiral tertiary alcohols

140.

anti-(S,Ss)-103 anti-(S,Ss)-138

R2Ph

HO R1

Alkylation

140

SPh

CbO H

O

SPh

CbO R1

O

Ph

CbO R1

MgCl

Ph

CbO R1

B(pin)

R2

i-PrMgCl

THF, rt, 1 min

B(pin)R2

(S)-139

2. H2O2, NaOH

1. reflux, 16 h

Scheme 2.39


64

We began by investigating the alkylation of sulfoxide anti-rac-103 using lithium amide

bases.120,132

α-Deprotonation of anti-rac-103 using LDA in THF at −78 °C for 10

minutes and trapping with methyl iodide gave diastereomeric sulfoxides rac-141a and

rac-141b in 49% and 35% yield respectively (Scheme 2.40). It was not possible to

calculate the diastereomeric ratio from the 1H NMR spectrum of the crude product. The

relative stereochemistry has not been determined. Isolation of diastereomeric sulfoxides

indicates that either the reaction proceeds via a planar carbanion or that the lithiated

intermediate is configurationally unstable. A similar phenomenon was observed by

Hoppe in the lithiation-trapping of benzylic O-alkyl carbamates (see Schemes 1.5 and

1.6).23

1. LDA, THF_78 °C, 10 min

2. MeI

rac-141a, 49%rac-141b, 35%

ant i-rac-103

SPh

O

CbO H

SPh

O

CbO Me

Scheme 2.40

We attempted to improve the diastereoselectivity of the alkylation by using dimethyl

sulfate as the methylating agent (Scheme 2.41). From this reaction sulfoxide rac-141a

was isolated in 54% yield and rac-141b was isolated in 28% yield.

SPh

O

CbO Me

rac-141a, 54%rac-141b, 28%

1. LDA, THF_78 °C, 10 min

2. Me2SO4

ant i-rac-103

SPh

O

CbO H

Scheme 2.41

In addition, we investigated using alternative amide bases (Scheme 2.42). First,

deprotonation by LiHMDS and trapping with methyl iodide gave sulfoxides rac-141a

and rac-141b in disappointing yields (29% and 16% yield respectively). Use of

KHMDS and trapping with methyl iodide gave none of the desired products and starting

material was recovered in 87% yield.


65

SPh

O

CbO Me

rac-141a, 29%rac-141b, 16%

1. LiHMDS, THF_78 °C, 10 min

2. MeI

+ RSM 87%

ant i-rac-103

SPh

O

CbO H

1. KHMDS, THF_78 °C, 10 min

2. MeI

ant i-rac-103

SPh

O

CbO H

rac-141a, 0%rac-141b, 0%

SPh

O

CbO Me

Scheme 2.42

In conclusion, we have been able to synthesise diastereomeric sulfoxides rac-141a and

rac-141b in modest yields. We have been unable to significantly improve the

diastereoselectivity within the alkylation procedure.

With sulfoxides rac-141a and rac-141b in hand, sulfoxide → magnesium exchange

chemistry was attempted in order to synthesise tertiary alcohols. Therefore, sulfoxide

rac-141a was treated with i-PrMgCl in THF at room temperature for 1 minute and

trapped with methyl chloroformate (Scheme 2.43). Unfortunately, ester rac-142 was

not formed and the 1H NMR spectrum of the crude product showed a complex mixture

of products. Purification by flash column chromatography gave no identifiable

products. No starting material was remaining at the end of the reaction and sulfoxide

rac-128, the by-product of sulfoxide → magnesium exchange, was not formed.

rac-141a

SPh

O

CbO Me

Ph

Me OCb

OMe

O

1. i-PrMgClTHF, rt, 1 min

2. MeOCOCl

rac-142

S

O

rac-128Not Formed

Scheme 2.43

We postulated that the Grignard intermediate may be chemically unstable at high

temperature. A similar phenomenon has been observed in the lithiation of O-alkyl

carbamates due to 1,2-carbamoyl migration.73

Therefore, we reduced the temperature of

the sulfoxide → magnesium exchange reaction to −78 °C (Scheme 2.44).


66

Unfortunately, the reaction again gave a complex mixture of unidentified products by

1H NMR spectroscopy of the crude mixture.

rac-141a

SPh

O

CbO Me

Ph

Me OCb

OMe

O

1. i-PrMgCl, THF,_78 °C 1 min

2. MeOCOCl

rac-142Not Formed

S

O

rac-128Not Formed

Scheme 2.44

We postulated that the inability to form the desired product could be due to the choice

of electrophile. Therefore, we attempted to trap with benzaldehyde or quench the

exchange reaction with methanol (Scheme 2.45). In each case the desired products,

alcohols rac-143 or carbamate rac-144 respectively, were not isolated.

rac-141a

SPh

O

CbO Me

Ph

Me OCb

Ph

OH

1. i-PrMgCl, THF_78 °C, 1 min

2. PhCHO or MeOH

rac-143Not Formed

Ph

Me OCb

Hor

rac-144Not Formed

Scheme 2.45

Finally, we turned to sulfoxide → lithium exchange to see if the problems were due to

the organometallic reagent. n-BuLi was added to sulfoxide rac-141a at −78 °C in THF

and trapping with methyl chloroformate gave a complex mixture of products (Scheme

2.46). In addition, quenching the sulfoxide → lithium exchange with MeOH also gave

an unidentified mixture of products.

rac-141a

SPh

O

CbO Me

rac-142Not Formed

rac-144Not Formed

Ph

Me OCb

OMe

O

1. n-BuLi, THF_78 °C, 1 min

2. MeOCOCl or MeOHPh

Me OCb

Hor

Scheme 2.46


67

To conclude, we have been unable to find conditions to carry out a sulfoxide →

magnesium exchange of sulfoxide rac-141a. Unfortunately, all attempts have led to a

complex mixture of products being formed. In addition, using n-BuLi to carry out a

sulfoxide → lithium exchange was unsuccessful. Therefore, boronate rearrangements

have not been attempted.


68

2.5 Conclusions and Future Work

A procedure for the synthesis of α-alkoxy Grignard reagents in 99:1 er has been

successfully developed. The method begins with asymmetric lithiation of O-alkyl

carbamate 14 and trapping with Andersen’s sulfinate (SS)-97 to give diastereomeric

sulfoxides anti-(S,SS)-103 and syn-(R,SS)-103. Interestingly, a loss of enantiomeric ratio

is observed on trapping and we have shown that this is due to sulfoxide → lithium

taking place under the lithiation-trapping conditions. Thus, a reverse addition protocol

(addition of the intermediate organolithium to Andersen’s sulfinate (SS)-97) was utilised

to improve the enantiomeric ratio of the products. Furthermore, use of chiral diamine

ligands allows for the isolation of either sulfoxide anti-(S,SS)-103 or sulfoxide syn-

(R,SS)-103 in 99:1 er via chiral amplification. Significantly, the procedure does not

require the use of (−)-sparteine.

Then, a sulfoxide → magnesium exchange protocol was employed to generate α-alkoxy

Grignard reagents. The optimised conditions were 2.5 eq. of i-PrMgCl in THF at room

temperature for 1 minute. Trapping with electrophiles gave an array of α-substituted

products in 99:1 er. For example, ester (R)-126 was formed in 41% yield and 99:1 er

over two steps from O-alkyl carbamate 14 (Scheme 2.47). Furthermore, our work is the

first example of a sulfoxide → magnesium exchange process occurring at room

temperature. Of particular note, α-alkoxy Grignard reagents have been shown to be

configurationally stable for up to 30 minutes at room temperature.

SPh

O

CbO H

anti-(S,SS)-103

56%, 99:1 er

THF, rt,1 min,

then MeOCOCl

i-PrMgClPh

CbO H

(R)-126, 73%

OMe

O

Ph OCb

1. s-BuLi, (R,R)-42

Et2O, _78 °C, 1 h

2.

14

Cb = CONiPr2S

O

O

(SS)-97


Scheme 2.47

The synthesis of tertiary alcohols via sulfoxide → magnesium exchange was attempted.

Sulfoxide anti-rac-103 was alkylated using LDA and methyl iodide to give a mixture of

diastereomeric sulfoxides rac-141a and rac-141b. Unfortunately all attempts to


69

conduct a sulfoxide → magnesium exchange on these substrates were unsuccessful. In

addition, sulfoxide → lithium exchange using n-BuLi in THF at −78 °C gave a complex

mixture of unidentified products.

Future work would see the expansion of our methodology to include other O-alkyl

carbamates and esters. This would allow an array of α-alkoxy Grignard reagents to be

synthesised in ≥99:1 er. One system of interest is ester 145 which was reported by

Aggarwal in 2012.133

Ester 145 has been shown to be superior in the lithiation-boronate

rearrangement methodology to carbamates. However, lithiation of ester 145 using s-

BuLi/(−)-sparteine only give products in ≤96:4 er. Therefore, using our method to

generate α-alkoxy Grignard reagent (S)-147 in 99:1 er from sulfoxide anti-(S,SS)-146

would provide significant benefits (Scheme 2.48).

ant i-(S,SS)-146

SPh

O

O H

Ph

Ar

O

MgClPh

O HAr

O

(S)-147145

OAr

O1. s-BuLi, Ligand

Et2O, _78 °C, 1 h

SO

O

(SS)-97

2.

i-PrMgCl

THFrt, 1 min

Ar = 2,4,6-(iPr)3C6H2

99:1 er 99:1 er

Scheme 2.48

Chapter Three: Synthesis and Reactions of α-Amino Grignard Reagents

70

Chapter Three: Synthesis and Reactions of α-Amino

Grignard Reagents

Described in this chapter are our efforts towards the synthesis of chiral α-amino

Grignard reagents. Of particular interest was the formation of pyrrolidinyl sulfoxides

anti-(S,SS)-148 and syn-(R,SS)-148 and piperidinyl sulfoxides anti-(S,SS)-149 and syn-

(R,SS)-149 in ≥99:1 er (Scheme 3.1). It was proposed that lithiation of N-Boc

pyrrolidine 39 or N-Boc piperidine 48 and trapping with Andersen’s sulfinate (SS)-97

would provide an expedient route to the desired sulfoxides.

NBoc

S

O

pTolH

S

O

pTolNBoc

H

ant i-(S,Ss)-148

NBoc

S

O

pTolH

syn-(R,Ss)-148

S

O

pTolNBoc

H


NBoc

NBoc

SO

O

(SS)-97

SO

O

(SS)-97

+

+

39

48

Scheme 3.1

Subsequently, a sulfoxide → magnesium exchange protocol would be developed to

synthesise Grignard reagents in high yield and enantioselectivity. For example,

Grignard reagent (S)-150 would be formed from anti-(S,SS)-148 and its enantiomer, (R)-

150, would be synthesised from syn-(R,SS)-148 (Scheme 3.2).

NBoc

S

O

pTolH

anti-(S,Ss)-148

NBoc

S

O

pTolH

syn-(R,Ss)-148

i-PrMgCl

THF 0 °C

i-PrMgCl

THF 0 °C

NBoc

H

NBoc

H

MgCl

MgCl

(S)-150

(R)-150

Scheme 3.2


71

3.1 Previous Syntheses of α-Amino Sulfoxides, Sulfides and Sulfones

Surprisingly, the synthesis of simple cyclic N-Boc α-amino sulfoxides, such as 148 and

149 (Figure 3.1), has not been reported previously. Therefore, in this section a short

review of the known methods of synthesising cyclic α-amino sulfides and sulfones is

presented. In addition, the syntheses of two structurally related α-sulfinyl lactams are

discussed.

NBoc

S

O

pTolH

S

O

pTolNBoc

H

148 149

Figure 3.1

There are three general synthetic strategies towards cyclic α-amino sulfides: (i)

deprotonation of N-Boc heterocycles and trapping with disulfides; (ii) addition of thiols

to cyclic iminium ions; (iii) Pummerer rearrangement of amino sulfoxides.

In 1989, Beak and Lee reported the lithiation of N-Boc piperidine 48 and trapping with

diphenyl disulfide to give sulfide 151 in 61% yield (Scheme 3.3).134

This reaction

proceeds via organolithium reagent rac-59. Since then, this approach has been

expanded to include a number of N-Boc heterocycles, including imidazolidines135

and

pyrimidines.136

NBoc

NBoc

SPh

1. s-BuLi, TMEDA,

Et2O, _78 °C, 6 h

2. PhSSPh

48 151, 61%

NBoc

Livia

rac-59

Scheme 3.3

Another popular method of synthesising α-amino sulfides is the addition of thiols to

cyclic iminium ions. For example, Huang et al. reported the acid-catalysed elimination

of hydroxy pyrrolidine 152 in the presence of 2-mercaptopyridine gave sulfide 153 in

90% yield (Scheme 3.4).137

This reaction proceeds via iminium ion 154. A similar

approach has also been described by Chiba and co-workers to synthesise 2,5-subsituted

pyrrolidines.138


72

NHS

NBoc

OTBDMS

S NNBoc

OTBDMS

OH PPTS-TsOH

CH2Cl2, rt, 1 d

(S)-153, 90%152

NBoc

OTBDMS

v ia

154

Scheme 3.4

Cyclic α-amino sulfides have also been synthesised via an intramolecular Pummerer

rearrangement.139

Sulfoxide 155 was treated with O-silylated ketene acetal 156 (which

acts as an O-silylation reagent) in the presence of catalytic zinc iodide (Scheme 3.5).

The reaction proceeded via adduct 158 and gave sulfide 157 in 57% yield.

viaNAc

SPh

NH S

O

Ph

Ac

155

MeO OTBDMS

0.1 eq. ZnI2CH3CN, rt, 25 h

157, 57%

NH SPh

Ac

158

156

Scheme 3.5

The Pummerer rearrangement was also found to be an expedient method for

synthesising indolizidine sulfides 160.140

Treatment of amino sulfoxides 159 with O-

silylated ketene acetal 156 and catalytic zinc iodide gave indolizidine sulfides 160 in

85% yield (Scheme 3.6). In addition, subsequent oxidation of 160 by m-CPBA formed

sulfones 161 in 30% yield. Presumably the oxidation proceeds via a sulfoxide

intermediate.

NH

O S Ph

O

N

SPhO0.1 eq. ZnI2

CH3CN, rt, 24 h

MeO OTBDMS

159 160, 85%

N

SO2PhO

mCPBA

CH2Cl2, rt, 16 h

161, 30%

156

HHH

Scheme 3.6

Furthermore, 2-sulfonyl pyrrolidines have also been successfully synthesised. For

example, Ley and co-workers reported the synthesis of a number of cyclic α-amino

sulfones.141

The typical synthetic procedure is shown in Scheme 3.7 whereby methoxy

N-formyl pyrrolidine 162 was treated with benzenesulfinic acid. This reaction

presumably proceeds via iminium adduct 164 to give sulfone 163 in 89% yield.


73

N

H O

OMe

164

N

H O

SO2Ph

163, 89%

N

H O

S

O

OH via

162

CH2Cl2, rt, 20 h

Scheme 3.7

Whilst there are no simple α-amino sulfoxides reported in the literature, two lactams

have been reported bearing an α-amino sulfoxide moiety. Thomas et al. synthesised

pyrrolizidinone sulfoxides 166 in 80% yield by oxidation of sulfides 165 using mCPBA

(Scheme 3.8).142

N

O S Me

N

O S

OMe

H

mCPBA

CH2Cl2, 0 °C, 1 h

165 166, 80%

H H

Scheme 3.8

Finally, a number of syntheses of 2-sulfinyl azetidinones have been reported due to

them being a common intermediate for the synthesis of penem-derived antibiotics.143,144

Typically, their synthesis involves oxidation of the sulfide precursor as shown in

Scheme 3.9.145

Oxidation of sulfide 167 using sodium periodate in aqueous methanol

gave a mixture of diastereomeric sulfoxides 168 in 93% yield.

MeOH/H2O, rt, 1 hNO S

NO S

O

HNaIO4

168, 93%167 Scheme 3.9

To summarise, there are no examples of simple α-amino sulfoxides such as 148 and 149

reported in the literature. In contrast, a number of methods to synthesise α-amino

sulfides and sulfones have been described.


74

3.2 Attempted synthesis of Pyrrolidinyl and Piperidinyl α-Amino

Sulfoxides

At the start of our project, there were no examples of compounds containing the N-Boc-

α-sulfinyl motif reported in the literature. Despite this, we postulated that sulfoxides

anti-(S,SS)-148 and syn-(R,SS)-148 could be synthesised by lithiation of N-Boc

pyrrolidine 39 and trapping with Andersen’s sulfinate (SS)-97 (Scheme 3.10).

Furthermore, we expected that this methodology could be easily expanded to include

other N-Boc heterocycles.

NBoc

1. s-BuLi, Ligand,

Et2O, _78 °C

2.

39

NBoc

S

O

H

(S,Ss)-148

NBoc

S

O

H

(R,Ss)-148SO

O

(SS)-97

Scheme 3.10

3.2.1 Attempted Synthesis of Pyrrolidinyl and Piperidinyl α-Amino Sulfoxides via

Lithiation-Trapping

We began our investigation with the racemic lithiation of N-Boc pyrrolidine 39 and

trapping with methyl p-toluenesulfinate 121. N-Boc pyrrolidine 39 was lithiated using a

diamine-free racemic lithiation protocol developed within our group (s-BuLi, THF, −78

°C, 1 hour).146

However, trapping with sulfinate 121 did not give the expected

diastereomeric sulfoxides anti-rac-148 and syn-rac-148 (Scheme 3.11). Instead, after

column chromatography, we isolated dihydropyrrole 169 in 31% yield. Key

spectroscopic data that allowed the structure of dihydropyrrole 169 to be identified

include two alkene signals at δc 143.8 (quaternary C) and 124.2 (CH) in the 13

C NMR

spectrum and an alkene CH signal (δH 5.99) in the 1H NMR spectrum. Compound 169

also gave satisfactory HRMS data. In addition, N-Boc pyrrolidine 39 was recovered in

43% yield from this reaction.


75

NBoc

NBoc

S

O

pTol

1. 1.3 eq s-BuLi,

THF, _78 °C, 1 h

2. NBoc

S

O

pTol

ant i-rac-14839

Not Formed

SOMe

O

H

NBoc

S

O

pTolH

syn-rac-148

121

169, 31%

Scheme 3.11

The racemic lithiation of N-Boc piperidine 48 and trapping with methyl

benzenesulfinate 170 was also attempted. In this case, the lithiation conditions were s-

BuLi/TMEDA in Et2O at −78 °C for 3 hours147

since the diamine free protocol does not

lithiate N-Boc piperidine 48.146

The expected sulfoxides anti-rac-149 and syn-rac-149

were not formed and tetrahydropyridine 171 was isolated in 13% yield (Scheme 3.12).

This product was identified by two alkene signals (δc 143.5 and 113.7) in the 13

C NMR

spectrum and an alkene CH signal (δH 6.37, triplet) in the 1H NMR spectrum. N-Boc

piperidine 48 was also recovered in 52% yield.

NBoc

1. 1.3 eq s-BuLi/TMEDA

Et2O, _78 °C, 3 h

2.NBoc

SPh

O

NBoc

SPh

O

48S

OMe

O

syn-rac-149 171, 13%

170

NBoc

SPh

O

H H

ant i-rac-149

Not Formed

Scheme 3.12

In response to these disappointing results, we postulated two mechanisms for the

formation of dihydropyrrole 169 and tetrahydropyridine 171. These are summarised in

Schemes 3.13, 3.14 and 3.15 for the pyrrolidine system. In the first mechanism,

lithiation and electrophilic trapping would give sulfoxides 148, which could then

undergo elimination via a cycloreversion process to give dihydropyrrole 172 (Scheme

3.13). Vinylic lithiation of adduct 172 as reported by Beak in 1993148

and subsequent

trapping with sulfinate 121 would give dihydropyrrole 169. Although cycloreversion of

sulfoxides is a well-established procedure for the synthesis of carbon-carbon double

bonds,149-151

it is typical for elimination of aryl sulfinates to proceed at temperatures of

25-80 °C.152

Therefore, it is possible that this mechanism may not be occurring under

our low temperature conditions.


76

NBoc

S

O

pTolNBoc

H

S pTol

OH

Base

148 169

NBoc

1. s-BuLi, THF

2. Sulfinate 121

39

NBoc Sulfinate 121

172

Scheme 3.13

Alternatively, due to the increased acidity of the α-proton in sulfoxide 148, a second

deprotonation and trapping could occur to give adduct 173. This disubstitution could

increase the propensity for a cycloreversion to occur to give dihydropyrrole 169

(Scheme 3.14). Doubly, α,α-substituted products of lithiation-trapping reactions

analogous to 173 have been previously seen within the group when methyl

chloroformate was used as the electrophile.146

NBoc

S

O

pTolNBoc

S

O

pTolNBoc S

O

pTol

S pTol

OH

HBase

148 173 169

NBoc

1. s-BuLi, THF

2. Sulfinate 121

39

Sulfinate 121

Scheme 3.14

The second mechanism is dependent upon the α-elimination of the sulfoxide moiety by

the nitrogen lone pair. In this process, sulfoxide 148 would be formed by lithiation-

trapping and subsequent α-elimination would give iminium ion 174. Deprotonation of

the β-proton would lead to the formation of dihydropyrrole 172. This could undergo

vinylic lithiation148

and trapping with sulfinate 121 would then give dihydropyrrole 169

as with the cycloreversion mechanism (Scheme 3.15). It is worth noting that α-amino

sulfones are commonly used as iminium ion precursors although this is usually

conducted in the presence of a Lewis acid.141,153

NBoc

S

O

pTolNBoc

NBoc

148 174 172

H

NBoc

169

S

O

pTolBase Base

Sulfinate 121

B

Scheme 3.15


77

It is possible that the conformation of sulfoxides 148 and 149 may cause α-elimination

to be favoured (Figure 3.2). To avoid steric interaction between the sulfoxide and the

planar NCO moieties (1,3-allylic type strain),154

the sulfoxide occupies the axial

position. This causes an alignment between the N-lone pair orbital and the anti-bonding

σ*C-S orbital and hence elimination is potentially favoured.

Figure 3.2

Both of the proposed mechanisms require an excess of base to be present within the

reaction mixture. Therefore, a reverse addition protocol was explored in which lithiated

N-Boc pyrrolidine was added to sulfinate 121. This ensured that there was never an

excess of base during the electrophilic trapping step. From this reaction, a reduction in

the yield of dihydropyrrole 169 (10%) was observed. However, hydroxy pyrrolidine

175 was now isolated as the major product in 52% yield (Scheme 3.16). The desired

sulfoxides anti-rac-148 and syn-rac-148 were not evident in the 1H NMR spectrum of

the crude product.

NBoc

S

O

pTol

anti-rac-148

Not Formed

H

NBoc

S

O

pTolH

syn-rac-148

NBoc

1. s-BuLi,

THF, _78 °C, 1 h

2. NBoc

S

O

pTolNBoc

OH

Reverse Addition

39 169, 10% 175, 52%

SOMe

O

121

Scheme 3.16

Hydroxy pyrrolidine 175 could be formed by either of the elimination processes

previously discussed. These mechanisms assume the initial formation of sulfoxide 148

and are summarised in Scheme 3.17. In the case of α-elimination of the sulfoxide from

148 by the nitrogen lone pair, iminium ion 174 would be formed. Iminium ion 174 may

then be quenched with water during the aqueous work-up to give hydroxy pyrrolidine


78

175. On the other hand, cycloreversion of the sulfoxide from 148 would give

dihydropyrrole 172. Protonation on work up could lead to the formation of iminium ion

174 which would be quenched to give hydroxy pyrrolidine 175 as previously discussed.

NBoc

S

O

pTol

NBoc

NBoc

OHH2O

148 174 175

NBoc

H

S pTol

OH

172

NBoc

148

H

-Elimination

Cycloreversion

H

Scheme 3.17

Chiral diamines can modulate the reactivity of organolithium reagents. Therefore, we

hoped that use of (−)-sparteine may hinder the formation of formation of dihydropyrrole

169. Unfortunately, lithiation of N-Boc pyrrolidine 39 using s-BuLi/(−)-sparteine and

trapping with sulfinate 121 gave dihydropyrrole in 13% yield. N-Boc pyrrolidine 39

was recovered in 65% yield (Scheme 3.18).

NBoc

S

O

pTol

ant i-rac-148

Not Formed

H

NBoc

S

O

pTolH

syn-rac-148

NBoc


Et2O, _78 °C, 3 h

2. NBoc

S

O

pTol

39 169, 13%

SOMe

O

121

Scheme 3.18

As an aside, attempts were made to improve the yield of dihydropyrrole sulfoxide 169.

The formation of dihydropyrrole sulfoxide 169 requires at least two equivalents of base

and sulfinate 121 and therefore, the amount of s-BuLi and methyl p-toluene sulfinate

121 was increased. Lithiation of N-Boc pyrrolidine 39 with 2.5 eq. of s-BuLi in THF

and trapping with 3 eq. of 121 gave dihydropyrrole sulfoxide 169 in 44% yield (Scheme

3.19). This is compared to 31% yield when 1.3 eq. of s-BuLi and 2 eq. of 121 were

used (see Scheme 3.11).


79

NBoc

1. 2.5 eq s-BuLi,

THF, _78 °C, 1 h

2. 3 eq. NBoc

S

O

pTol

39S

OMe

O

121

169, 44%

Scheme 3.19

As a further attempt to synthesise N-Boc heterocyclic sulfoxides via direct lithiation and

electrophilic trapping, more electron-rich aryl sulfinates and alkyl sulfinates were used

with the aim of reducing the leaving group capability of the sulfoxide. In particular,

alkyl sulfinates are known to require temperatures of up to 130 °C to facilitate sulfoxide

elimination via a cycloreversion process.152

First, methyl p-methoxybenzenesulfinate

177 was synthesised in two steps from p-methoxybenzenethiol in 91% overall yield

(Scheme 3.20).119,155

Next, we targeted methyl t-butylsulfinate 179. Unfortunately, the

synthesis of sulfinate 179 from t-butyldisulfide 178 using the Meyers procedure (Br2,

Na2CO3, MeOH)119

was unsuccessful, with the reaction returning unreacted starting

disulfide 178. However, sulfinothioate 180 was successfully synthesised by oxidation

of t-butyldisulfide 178 with 30% hydrogen peroxide via a known procedure.156

We

reasoned that sulfinothioate 180 could be used in an analogous way to sulfinate 179.

SS

180, 85%

SS

O30% H2O2(aq)

AcOH, rt, 15 h

178

SS

SOMe

OBr2, NaCO3

MeOH, rt, 3 h

178 179

SH

MeO

S

MeO

S

MeO

S

OMe

OMe

O

NaBO3.4H2O

MeOH-H2O, rt, 2 h

Br2, Na2CO3

MeOH, rt, 3 h

176, 97% 177, 94%

Scheme 3.20

With sulfinate 177 and sulfinothioate 180 in hand, the lithiation and electrophilic

trapping of N-Boc pyrrolidine 39 was attempted. Lithiation was carried out using s-


80

BuLi in THF and when using sulfinate 177 as the electrophile, sulfoxides 181 were not

formed. However, there was limited evidence of a small amount of dihydropyrrole 182

in the 1H NMR spectrum of the crude product (δH 5.96 ppm, double doublet, =CH).

However, it was not possible to isolate dihydropyrrole 182 after flash column

chromatography. In this case, starting N-Boc pyrrolidine 39 was recovered in 84%

yield. The reaction using sulfinothioate 180 gave sulfide 184 in 15% yield (formed by

preferential attack of the lithiated N-Boc pyrrolidine at the sulfanyl centre) and

recovered starting N-Boc pyrrolidine 39 in 74% yield (Scheme 3.21). There was no

evidence for the formation of the desired sulfoxides 183.

NBoc

NBoc

S

O

1. s-BuLi,

THF, _78 °C, 1 h

2. NBoc

S

O

39 181, 0% 182, trace

OMe OMe

NBoc

NBoc

S

O

1. s-BuLi,

THF, _78 °C, 1 h

2. NBoc

S

39 183, 0% 184, 15%

SS

O

180

S

MeO

OMe

O

177

H

H

+ 84% RSM

+ 74% RSM

Scheme 3.21

To conclude, we have been unable to synthesise pyrrolidinyl α-amino sulfoxides 148 via

lithiation and trapping with sulfinate 121. In all cases, dihydropyrrole 169 or hydroxy

pyrrolidine 175 were formed in modest yields. Similarly, trapping with alternative

sulfinates was unsuccessful. Furthermore, piperidinyl α-amino sulfoxides 149 were not

formed by our lithiation-trapping procedure. Instead, tetrahydropyridine 171 was

isolated as the major product.

3.2.2 Attempted synthesis of Pyrrolidinyl and Piperidinyl α-Amino Sulfoxides via

Oxidation of Sulfides

Due to the lack of success with the sulfinate trapping, our attention then turned to the

lithiation and electrophilic trapping with disulfides followed by a subsequent oxidation


81

to form the desired N-Boc-α-sulfinyl heterocycles. Investigation of this alternative

route would also allow us to further investigate whether the desired N-Boc-α-sulfinyl

heterocycles are inherently unstable or if the instability is due to the conditions used for

the lithiation and electrophilic trapping.

First, α-amino sulfides were synthesised using a known procedure (see Scheme 3.3).147

Indeed, lithiation-trapping of N-Boc piperidine 48 was carried out in the same fashion

(s-BuLi, TMEDA, Et2O, −78 °C, 3 hours) to give sulfide 151 in 63% yield (Scheme

3.22). With N-Boc pyrrolidine 39, lithiation using s-BuLi in THF (−78 °C, 1 hour)

worked well and the lithiated intermediate was trapped with a number of alky and aryl

disulfides giving sulfides 184-187 in 14-59% yield.

NBoc

NBoc

SR

1. s-BuLi,

THF, _78 °C, 1 h

2. RSSR

39 n = 148 n = 2

185, R = Ph, 44 %186, R = pTol, 52 %187, R = 4-MeOC6H4,14%184, R = CMe3, 59%

1. s-BuLi, TMEDA

Et2O, _78 °C, 3 h

2. PhSSPhNBoc

SPh

151, 63 %

n

Scheme 3.22

With sulfide 185 in hand, oxidation using mCPBA was attempted (Scheme 3.23, Table

3.1). Using conditions reported by Fodor and Feldman157

(mCPBA, Na2CO3, CH2Cl2,

room temperature), sulfoxides 188 were not formed (entry 1). However, hydroxy

pyrrolidine 175 (which had previously been isolated when using the reverse addition

protocol, see Scheme 3.16) was formed in 31% yield. Hydroxy pyrrolidine 175 could

have been formed by sulfoxide α-elimination as previously postulated. Alternatively,

over-oxidation to the sulfone may have occurred. This would act as a better leaving

group for decomposition by α-elimination by the nitrogen lone pair to give hydroxy

pyrrolidine 175 on work-up. In an attempt to ensure over-oxidation was prevented, a

protocol developed by Ramesh et al.158

(mCPBA, KF, CH3CN/H2O, rt) was employed.

However, this reaction still gave hydroxy pyrrolidine 175 in 57% yield (entry 2). A

lower temperature oxidation was also attempted following a known procedure93

(mCPBA, CH2Cl2, −40 °C) and this time hydroxy pyrrolidine 175 was isolated in 86%

yield (entry 3). In addition, this procedure was used for the oxidation of sulfides 186,


82

187 and 184, but sulfoxides 148, 181 and 183 were not formed and hydroxy pyrrolidine

175 was isolated in each case in 74-81% yield (entries 4-6).

NBoc

SR

Oxidant / Additive

Solvent, Temp. NBoc

S

O

RNBoc

OH

185, R = Ph186, R = pTol

187, R = 4-MeOC6H4

184, R = CMe3

188, R = Ph148, R = pTol

181, R = 4-MeOC6H4

183, R = CMe3

175

Not Formed

H

Scheme 3.23

Table 3.1: Oxidation of N-Boc 2-Sulfanyl Pyrrolidines

Entry Sulfide Oxidant Additive Solvent Temp

/ °C

Yield of

175 / %

1 185 mCPBA Na2CO3 CH2Cl2 rt 31

2 185 mCPBA KF MeCN/H2O rt 57

3 185 mCPBA - CH2Cl2 −40 86

4 186 mCPBA - CH2Cl2 −40 81

5 187 mCPBA - CH2Cl2 −40 74

6 184 mCPBA - CH2Cl2 −40 77

7 186 H2O2 - HFIP rt 43

8 186 Me3SiCl/KO2 - CH3CN −15 52

As oxidation using mCPBA did not give the desired sulfoxide products, alternative

oxidation methods were attempted with sulfide 186. These included, a procedure

published by Bonnet-Delpon et al. that uses hydrogen peroxide in

hexafluoroisopropanol (HFIP),159

and a protocol devised by Huang and co-workers

mediated by trimethylsilyl chloride and potassium superoxide.160

Both these methods

also gave hydroxy pyrrolidine 175 in 43% and 52% yield respectively (entries 7 and 8).

To conclude, lithiation-trapping of N-Boc pyrrolidine 39 and N-Boc piperidine 48 with

disulfides was successful giving a number of α-sulfanyl N-Boc heterocycles.

Unfortunately, oxidation of these products proved to be unsuccessful, with the reaction

instead giving good yields of hydroxy pyrrolidine 175.


83

3.3 Attempted Synthesis of Cyclic and Acyclic α-Amino Sulfoxides

We wanted to further investigate whether the instability of N-Boc α-amino sulfoxides is

due to a cycloreversion process or because of an α-elimination of the aryl sulfoxide by

the nitrogen lone pair. Therefore, a series of substrates that would allow these two

mechanisms to be probed were identified (Figure 3.3). Sulfoxides 189-191, with N-

amido and N-thioamido groups, were designed to have an increased electron

withdrawing effect on the nitrogen atom. It was hoped that the nitrogen lone pair would

be less available for α-elimination. In addition, azetidine sulfoxides 192 were designed

to have a reduced propensity for elimination via either of the pathways. This is due to

placing a double bond (an intermediate in both processes) in the four membered ring

would cause additional strain in the system. Finally, sulfoxides 193-196 have no β-

protons and, therefore, a cycloreversion of the sulfoxide moiety could not occur.

N

R X

S

O

pTolN S

pTol

OPMP

Ph

X

N SpTol

O

Boc

PMP

NBoc

SpTol

O

H

195 196189, R = CPh3, X = O190, R = CMe3, X = O191, R = CMe3, X = S

193, X = O194, X = S

N

S

SpTol

O

H

192

Figure 3.3

3.3.1 Attempted Synthesis of Cyclic N-Amido and N-Thioamide Sulfoxides

There are limited examples of lithiation-trapping of cyclic amides reported in the

literature. In 1981, Seebach and co-workers reported the lithiation and electrophilic

trapping at the α-position of the triphenylacetamides of azetidine 197, pyrrolidine 198

and piperidine 199.161

The amides were treated with t-BuLi in THF at −40 °C for 10

minutes, before being allowed to warm to 0 °C for a further 20 minutes. The lithiated

intermediates were then trapped with electrophiles to give α-substituted N-heterocycles

200-203 in 38-62% yield. Selected results are shown in Scheme 3.24. These lithiation-


84

trappings proceeded in modest yield but the main drawback of this procedure is the use

of pyrophoric t-BuLi.

N

Ph3C O2. PhCHO, t -BuCHO,

or Ph2CO

1. t-BuLi, THF,_40 °C to 0 °C, 30 min N

Ph3C O

n n

N

Ph3C O

200, 62%

Ph

OH N

Ph3C O

201, 38%

OH

N

Ph3C O

202, 52%

OH

Ph

Ph N

Ph3C O

203, 39%

Ph

OH

Ph

E

H H

197, n = 1198, n = 2199, n = 3

PhCHO t -BuCHO Ph2CO Ph2CO

Scheme 3.24

In 1984, Beak et al. described the s-BuLi/TMEDA-mediated lithiation of N-aryl

piperidine 204 (Scheme 3.25).162

Trapping with benzaldehyde or benzophenone gave

alcohols 205 or 206 respectively, both in 30% yield. The 2,4,6-triisopropylbenzamide

was chosen due to its sterically bulky nature, which hinders nucleophilic attack by s-

BuLi at the carbonyl group.

N

Ar O

2. PhCHO or Ph2CO

1. 1.3 eq. s-BuLi, TMEDA

THF, _78 °C, 5 h

204

Ar =N

Ar O

205, 30%

Ph

OH

N

Ar O

206, 30%

Ph

OH

PhH

PhCHO Ph2CO

Scheme 3.25

Our investigations focused on the lithiation-trappings of N-triphenylacetyl pyrrolidine

207 and N-pivaloyl pyrrolidine 209. First, lithiation and electrophilic trapping of N-

triphenylacetyl pyrrolidine 207 (prepared by acylation of pyrrolidine with pivaloyl

chloride) was attempted using similar conditions to those reported by Seebach and co-

workers (s-BuLi, THF, −40 °C, 3 hours).161

Unfortunately, when trapping with

sulfinate 121, sulfoxide 189 was not formed and sulfinamide 208 was isolated in 31%


85

yield (Scheme 3.26). Presumably, sulfinamide 208 is formed by initial nucleophilic

attack of s-BuLi at the amide carbonyl group, a phenomenon which has been previously

observed by Beak et al. in the attempted lithiation of amides derived from piperidine.162

The lithium amide this generates is then trapped by methyl p-toluenesulfinate 121 to

give 208.

N

Ph3C O

N

Ph3C O

2.

1. s-BuLi,

THF, _40 °C, 3 hN

SO

208, 31%207

S

O

189

H

S

O

OMe

121Not Formed

Scheme 3.26

The lithiation of N-pivaloyl pyrrolidine 209 was attempted at lower temperature and

using a chiral ligand (s-BuLi, (−)-sparteine, Et2O, −78 °C, 3 hours) (Scheme 3.27).

Disappointingly, electrophilic trapping with methyl p-toluenesulfinate 121 gave

sulfinamide 208 in 64% yield.

N

O

N

O

2.


Et2O, _78 °C, 3 hN

SO

208, 64%209 190

S

OS

O

OMe

121

H

Not Formed

Scheme 3.27

The lithiation-trapping of amides was unsuccessful due to nucleophilic addition of the

organometallic base to the amide carbonyl group. This problem has been seen

previously in the lithiation of amides by Beak et al.,162

therefore it may not be possible

to access amido sulfoxides 189 and 190 via lithiation chemistry.

It was hoped that the reduced electrophilicity of the thioamide functionality would

combat the problem of nucleophilic attack of s-BuLi at the carbonyl group of amides

207 and 209. Therefore, N-pivaloyl pyrrolidine 209 was treated with phosphorus(V)

sulfide in pyridine to give N-thiopivaloyl pyrrolidine 210 in quantitative yield. Initially,


86

N-thiopivaloyl pyrrolidine 210 was lithiated using conditions reported by Hodgson and

Kloesges for the lithiation of N-thiopivaloyl azetidine 101 (1.2 eq. s-BuLi, 2.4 eq.

TMEDA, THF, −78 °C, 3 hours),102

but after addition of different electrophiles

(benzaldehyde, p-tolyldisulfide or methyl p-toluenesulfinate 121) no trapped product

was observed and starting N-thiopivaloyl pyrrolidine 210 was recovered in high yield.

Therefore, the lithiation was repeated with 1.3 eq. of s-BuLi and TMEDA. This led to

the first example of a successful lithiation-trapping of N-thiopivaloyl pyrrolidine 210.

Electrophilic trapping with benzaldehyde gave a 60:40 mixture (by 1H NMR

spectroscopy) of diastereomeric alcohols syn-rac-211 anti-rac-211 which were isolated

in 31% and 27% yields respectively (Scheme 3.28). The assignment of the relative

stereochemistry of syn-rac-211 and anti-rac-211 and is presented in Chapter Four (see

Scheme 4.44).

N

S

N

S2. PhCHO


THF, _78 °C, 3 h

210

Ph

OH

N

S

Ph

OH

anti-rac-211, 27% syn-rac-211, 31%

H H

Scheme 3.28

Unfortunately, from the lithiation-trapping with methyl p-toluenesulfinate 121 under the

same lithiation conditions (1.3 eq. s-BuLi/TMEDA, THF, −78 °C, 3 hours), the desired

N-thiopivaloyl pyrrolidine sulfoxide 191 was not isolated. The 1H NMR spectrum of

the crude product showed trace amounts of dihydropyrrole 212 (δH 5.92, triplet, =C),

which could not be isolated by flash column chromatography. Starting thioamide 210

was recovered in 59% yield. In a similar way, when trapping with p-tolyldisulfide,

sulfide 213 was not formed and thioamide 210 was recovered in 78% yield (Scheme

3.29).


87

N

S

N

S

2.


THF, _78 °C, 3 h

210

S N

S

S

191 212, trace

O O

N

S

S

213

N

S

2. pTolSSpTol


THF, _78 °C, 3 h

210

H

SOMe

O

121

Not Formed

Not Formed

+ 78% RSM

+ 59% RSM

Scheme 3.29

Our attention turned to the synthesis of N-thiopivaloyl azetidine sulfoxides 192. It was

hoped that the four membered ring system would inhibit the sulfoxide elimination

allowing stable compounds to be isolated. We began our investigation with the

racemic lithiation of N-thiopivaloyl azetidine 101 (1.2 eq. s-BuLi, 2.4 eq. TMEDA,

THF, −78 °C, 30 min)102

and trapping with methyl p-tolyl sulfinate 121 (Scheme 3.30).

From this reaction, a 91:9 mixture of diastereomeric sulfoxides 192 were evident in the

1H NMR spectrum of the crude product. The NCH signal provided key diagnostic

information (δH 5.55, double doublet for the major diastereoisomer and δH 5.72, double

doublet for the minor diastereoisomer). However, after chromatography only the major

diastereomeric sulfoxide 192 was isolated in 9% yield. Unfortunately, the relative

stereochemistry was unable to be determined. In addition, N-thiopivaloyl azetidine 101

was recovered in 72% yield.

N

S

S

O

H

192, 9%

1. 1.2 eq. s-BuLi, 2.4 eq. TMEDA

THF, _78 °C, 30 min

2.N

S

101

SOMe

O

121

+ 72% RSM

Scheme 3.30

N-Thiopivaloyl azetidine sulfoxide 192 is the first example of an isolable α-amino

sulfoxide. We postulate that due to ring constraints both α-elimination and


88

cycloreversion are disfavoured. Furthermore, the thiopivalamide group provides an

increased electron withdrawing effect when compared to the Boc protecting group.

Thus, the nitrogen lone pair may be less available to eliminate the sulfoxide moiety.

It was hoped that the using a chiral ligand may improve the yield of the sulfoxide

products. It would also allow the assignment of the configuration in a similar fashion to

that of O-alkyl carbamate sulfoxides anti-(S,SS)-103 and syn-(R,SS)-103 (see Scheme

2.24). N-Thiopivaloyl azetidine 101 was lithiated using s-BuLi/(−)-sparteine in Et2O at

−78 °C and trapped with Andersen’s sulfinate (SS)-97 (Scheme 3.31). Unfortunately, no

product was evident in the 1H NMR spectrum of the crude product and N-thiopivaloyl

azetidine 101 was recovered in 85% yield.

N

S

S

O

H

N

S

S

O

H

(R,SS)-192(S,SS)-192


Et2O, _78 °C, 30 min

2.N

S

101 SO

O

(SS)-97

+ 85% RSM

Not Formed

Scheme 3.31

To conclude, we were able to successfully synthesise N-thiopivaloyl azetidine sulfoxide

192 by lithiation-trapping. However, the yield of the reaction was disappointing and

our attempts to increase the yield were fruitless. In contrast, pyrrolidinyl sulfoxides 191

were not formed from the lithiation of N-thiopivaloyl pyrrolidine 210 and trapping with

methyl p-toluene sulfinate 121.

3.3.2 Synthesis of Acyclic α-Amino Sulfoxides

The synthesis of sulfoxides without β-protons was targeted next and acyclic sulfoxides

193-196 were designed to probe this (Figure 3.4). This would allow us to explore

whether elimination was occurring via a cycloreversion process as well as varying the

electron withdrawing groups on the nitrogen atom.


89

N

Boc

S

196

O

N

O

Ph

OMe

S

193

N

S

Ph

OMe

S

194

N

O

tBuO

OMe

S

195

O O O

Figure 3.4

It was decided that the best route to sulfinyl benzamide 193 would be via alkylation of

N-PMP benzamide 214 with a chlorosulfide and subsequent oxidation. This route

avoids the use of lithiation chemistry which may result in nucleophilic attack of the

organolithium base at the carbonyl of the amide group. In 1972, Colonna et al.

reported that α-halogeno sulfoxides are unreactive towards nucleophilic substitution,

whereas nucleophilic substitution of α-halogeno sulfides is facile.163

Furthermore,

Hiyama and co-workers reported that alkylation of a similar N-PMP amide with

chloromethyl phenyl sulfide proceeds in 53% yield.164

To start with, benzamide 214 was synthesised by acylation of p-anisidine with benzoyl

chloride in 83% yield (Scheme 3.32).165

Then, alkylation of benzamide 214 with

chlorosulfide 215 (formed by reaction of methyl p-tolylsulfide and N-

chlorosuccinimide166

) was attempted. First, following Hiyama’s method (1.5 eq.

chlorosulfide 215, room temperature, 1 hour) gave sulfanyl benzamide 216 in 51% yield

(Table 3.2, entry 1). The alkylation was repeated using 2.0 eq. of chlorosulfide 215 over

18 hours and sulfanyl benzamide 216 was isolated in 62% yield (entry 2). The yield

was further improved by warming the reaction to 50 °C over the same time period. This

gave sulfanyl benzamide 216 in 68% yield (entry 3). A final attempt to optimise this

alkylation by increasing the amount of chlorosulfide 215 from 2.0 eq. to 2.5 eq. showed

no improvement in the yield of sulfanyl benzamide 216 (entry 4).


90

Et4N+I-, 50% NaOH(aq),

CH2Cl2,Temp, time

NH

O

Ph

OMe

N

O

Ph

OMe

SSCl

214, 83% 216

215NH2

OMe

PhCOCl, NaHCO3

CH2Cl2, 0 °C, 1 h

Scheme 3.32

Table 3.2: Optimisation of the alkylation of N-benzoyl anisidine 214

Entry Eq. Chlorosulfide 215 Temp. / °C Time / h Yield of 216 / %

1 1.5 rt 1 51

2 2.0 rt 18 62

3 2.0 50 18 68

4 2.5 50 18 68

Sulfanyl benzamide 216 was then oxidised using mCPBA (CH2Cl2, −40 °C, 1 hour) to

form sulfoxide 193 in 84% yield (Scheme 3.33). To our delight, α-amino sulfoxide 193

was stable and readily isolatable. Sulfoxide 193 has no β-protons and therefore

cycloreversion is not possible. In addition, the increased electron-withdrawing amide

group (when compared to Boc) on the nitrogen atom should reduce the propensity for α-

elimination of the aryl sulfoxide by the nitrogen lone pair. Therefore, the successful

isolation of α-amino sulfoxide 216 does not discriminate between the two proposed

mechanisms for the breakdown N-Boc α-sulfinyl heterocycles.

OmCPBAN

O

Ph

OMe

S

193, 84%

N

O

Ph

OMe

S

CH2Cl2, _40 °C, 1 h

216 Scheme 3.33

The thiobenzamide analogue, sulfoxide 194, was also synthesised via a similar route

(Scheme 3.34). This synthesis began with the conversion of benzamide 214 using


91

phosphorus(V) sulfide into thiobenzamide 217 which proceeded in a moderate 40%

yield.

Et4N+I-, 50% NaOH(aq),

CH2Cl2, 50 °C, 18 h

NH

S

Ph

OMe

N

S

Ph

OMe

SSCl

217, 40% 218, 54%

215

O

mCPBA

194, 77%

N

S

Ph

OMe

S

CH2Cl2,_40 °C, 1 h

NH

O

Ph

OMe

214

P2S5

Pyridine, 75 °C, 6 h

Scheme 3.34

Thiobenzamide 217 was then alkylated under our previously optimised conditions (2.0

eq. chlorosulfide 215, 50 °C, 18 hours) to give sulfanyl thiobenzamide 218 in 54%

yield. Finally, sulfanyl thiobenzamide 218 was oxidised using mCPBA to give

sulfoxide 194 in 77% yield. Sulfoxide 194 was our second example of an isolable

acyclic α-amino sulfoxide.

Attempts were also made towards the synthesis of N-Boc sulfoxide 195 but the routes

investigated were unsuccessful (Schemes 3.35 and 3.36). Initially, alkylation of N-Boc

p-anisidine 219 with chlorosulfide 215 using the modified Hiyama method164

(2.0 eq.

chlorosulfide 215, 50 °C, 18 hours) was investigated. Unfortunately, N-Boc sulfide 220

was not formed, and N-Boc p-anisidine 219 was recovered quantitatively (Scheme

3.35). Then, we attempted an alkylation which began with deprotonation of N-Boc p-

anisidine 219 using sodium hydride and subsequent addition of chlorosulfide 215. The

reaction did not produce any of the desired N-Boc sulfide 220 and N-Boc p-anisidine

219 was recovered in 100% yield. As a result, the planned oxidation to sulfoxide 195

could not be investigated.


92

Et4NI, 50% NaOH(aq),

CH2Cl2, 50 °C, 18h

NBoc

OMe

S

SCl215

O

195

NBoc

OMe

SNHBoc

OMe

219

1. NaH, 0 °C,15 min

2. 215, rt, 18 h 220, 0%

mCPBA

or

Scheme 3.35

Our attention then turned to the use of lithiation chemistry to access either N-Boc

sulfide 220 or N-Boc sulfoxide 194. N-Boc N-methyl p-anisidine 221 was synthesised

from N-Boc p-anisidine 220 by alkylation with methyl iodide, but subsequent lithiation-

trapping was unsuccessful (Scheme 3.36). When attempting to trap with p-tolyl

disulfide, a product was isolated, but we were unable to determine its structure (we do

not believe it to be the product of an ortho-lithiation). In addition, starting N-Boc N-

methyl p-anisidine 221 was recovered in 52% yield. Finally, when using methyl p-

toluenesulfinate 121 as the electrophile, sulfoxide 194 was not formed. In addition, N-

Boc N-methyl p-anisidine 221 was recovered in 83% yield. The reason for the failure of

these reactions is unclear.

NBoc

OMe

S

O

194, 0%

NBoc

OMe

S

NHBoc

OMe

219

NBoc

OMe

221, 98%

Me

NaH, MeI

THF, rt, 18 h

1. s-BuLi, TMEDA,

THF, _78 °C, 2 h

220, 0%

mCPBA

2. pTolSSpTol, 18 h

1. s-BuLi, TMEDA,

THF, _78 °C, 2 h

2. 121, 18 h

SOMe

O

121

Scheme 3.36


93

Unfortunately, the synthesis of N-Boc sulfoxide 194 was unsuccessful via alkylation

and when using lithiation chemistry. Currently, there is no evidence that this is because

the desired sulfoxide is unstable. Instead, it is suggested that these are not viable routes

to N-Boc sulfoxide 194.

Finally, we targeted N-Boc dimethylamine sulfoxide 196 as lithiation chemistry would

provide an expedient route to the desired compound. In 1989, Beak and Lee reported

the lithiation-trapping of N-Boc dimethylamine 222 to give substituted products in good

yield.147

In addition, Dieter and co-workers have also used the lithiation of N-Boc

dimethylamine 222 to exemplify coupling of α-lithio amines with aryl and vinyl

iodides.167,168

The lithiation of N-Boc dimethylamine 222 was carried out using conditions published

by Beak et al. (s-BuLi, TMEDA, Et2O, −78 °C, 2 hours).169

Trapping with methyl p-

toluene sulfinate 121 gave N-Boc dimethylamine sulfoxide 196 in 71% yield (Scheme

3.37). It should be noted that it was necessary that 1% Et3N to be added to the eluent for

chromatography to avoid decomposition on silica, possibly via silica-promoted α-

elimination of the sulfoxide group.

1. s-BuLi, TMEDA

Et2O, _78 °C, 2 h

2.

222

N

Boc

N

Boc

S

196, 71%

OS

OMe

O

121

Scheme 3.37

Sulfoxide 196 is the first example of an isolable compound containing the N-Boc-α-

sulfinyl motif. In contrast, our attempts to synthesise pyrrolidinyl sulfoxides 148 and

piperidinyl sulfoxides 149 were unsuccessful (see Schemes 3.11 and 3.12). Instead,

dihydropyrrole sulfoxide 169 and tetrahydropyridine sulfoxide 171 were isolated from

these reactions. We propose that the stability of sulfoxide 196 could be due to the

absence of β-protons in the molecule. Thus, cycloreversion of the sulfoxide moiety is

possible. However, as sulfoxide 196 is unstable on silica (in the absence of Et3N), we


94

cannot fully rule out α-elimination of the sulfoxide by the nitrogen lone pair as a cause

of the general instability of cyclic α-amino sulfoxides.

So far we have managed to synthesise one cyclic and three acyclic α-amino sulfoxides

either by lithiation-trapping or alkylation-oxidation (Figure 3.5). Disappointingly,

cyclic N-Boc α-amino sulfoxides 148 and 149 were not formed using a variety of

methods.

Stable Unstable

N

Boc

S

196

pTol

O

N

PMP

S

Ph SpTol

O

N

S

SpTol

O

H

192

N

PMP

O

Ph SpTol

O

193 194

NBoc

S

O

pTolH

S

O

pTolNBoc

H

148 149

Figure 3.5


95

3.4 Synthesis of Azabicyclo[3.1.0]hexane Sulfoxides

Our attention turned to designing a cyclic α-amino sulfoxide in which both α-

elimination and cycloreversion were disfavoured. An attractive option was the

synthesis of azabicyclo[3.1.0]hexanes sulfoxides syn-(R,R,Ss)-225 and anti-(S,S,Rs)-225.

From these substrates, sulfoxide elimination is prohibited due to Bredt’s rule.170,171

In

addition, we proposed that they could be expediently synthesised by lithiation of N-Boc

4-chloro or 4-tosyloxy piperidines 223 or 224 and trapping with Andersen’s sulfinate

(SS)-97 (Scheme 3.38). The lithiation-cyclisation of N-Boc 4-chloro and 4-tosyloxy

piperidines 223 and 224 has been previously studied by Beak et al. and the highest

enantioselectivity achieved in these lithiation processes were 78:22 er.41,172

Therefore,

we believed that our methodology could provide significant improvements in this arena.

N

X

Boc

223, X=Cl224, X=OTs

1. 2.2 eq. s-BuLi/diamine

Et2O, _78 °C, 1 h

2.S

O

SO

O

(SS)-97

syn-(R,R,SS)-225 ant i-(S,S,SS)-225

NBoc

S

O

NBoc

Scheme 3.38

Substituted azabicyclo[3.1.0]hexanes have been shown to have a wide range of

pharmacological activity. Indeed, they act as kinase and protease inhibitors173,174

and

also show good efficacy in the treatment of the hepatitis C virus.175

Furthermore, one

analogue, saxagliptin, has recently been approved in the treatment of type II diabetes

(Figure 3.6).176,177

OH

NNC

O

NH2

Saxagliptin

Figure 3.6


96

3.4.1 Lithiation-Trapping of N-Boc 4-Chloro and 4-Sulfonyl Piperidines

In 1994, Beak and co-workers reported the facile construction of azabicyclo[3.1.0]

hexanes in racemic fashion by the lithiation-cyclisation of N-Boc 4-chloro piperidine

223. Treatment of N-Boc 4-chloro piperidine 223 with 2.2 eq. of s-BuLi/TMEDA gave

2-substituted products 227, 229-232 in 36-75% yield (Scheme 3.39).178

This reaction

proceeds via α-lithiated piperidine 226 which immediately cyclises to give bicycle rac-

227. In 223, the chlorine atom will presumably be in the equatorial position and

equatorial α-lithiation will occur to give 2,4-cis-diastereoselectivity.179

In addition, the

intramolecular cyclisation occurs with inversion of configuration at the α-carbon to give

rac-227. Due to the increased acidity of the cyclopropanyl proton in rac-227 when

compared with starting piperidine 223, this second deprotonation event is favoured

leading to lithiated intermediate 228. Finally, trapping with an array of electrophiles

furnishes the desired 2-subsituted azabicyclo[3.1.0]hexanes 227, 229-232.

NBoc

Cl

H

NBoc

HNBoc

LiNBoc

E

s-BuLiTMEDA

s-BuLi/TMEDAE+

223

rac-227rac-228

NBoc

NBoc

SiMe3 NBoc

NBoc

Me NBoc

Ph

OHPh

rac-229, 62%

E+ = Me3SiCl

rac-230, 58%

E+ = Allyl-Br

rac-231, 36%

E+ = MeI

rac-232, 65%

E+ = Ph2CO

rac-227, 75%

E+ = H+

NCl

H

O

t-BuO

H

H

NCl

H

O

t-BuO

Li

H

226

cis-2,4-lithiation

inversionat C-Li

H

H

Scheme 3.39

Two years later, Beak and Park investigated the asymmetric lithiation-trapping of 4-

chloro piperidine 223.172

Lithiation of N-Boc 4-chloro piperidine 223 with 2.2 eq. s-

BuLi/(−)-sparteine in Et2O at −78 °C and trapping with trimethylsilyl chloride gave

bicycle rac-229 in 71% yield but 50:50 er (Scheme 3.40 and Table 3.3, entry 1). This

is a surprising result given that lithiation of N-Boc piperidine with s-BuLi/(−)-sparteine


97

and trapping with electrophiles is known to give a 2-subsituted product in low yield but

good enantioselectivity (87:13 er).41

In an attempt to overcome this problem, Beak and

Park studied whether the leaving group affected the enantioselectivity of the

intramolecular cyclisation. Lithiation of tosylate 224 with 2.2 eq. s-BuLi/(−)-sparteine

at −78 °C in Et2O and trapping with trimethylsilyl chloride gave bicycle (R,R)-229 in

good yield (77%) and satisfactory enantioselectivity (78:22 er) (entry 2).

N

X

Boc

N

Boc

SiMe3

(R,R)-229

1. 2.2 eq. s-BuLi/(_)-sparteine

solvent, temp., 4 h

2. Me3SiCl

223, X=Cl224, X=OTs233, X=ONs Ns = 4-NO2C6H4SO2

Scheme 3.40

Table 3.3: Asymmetric lithiation-cyclisation of 4-subsituted piperidines

Entry SM Solvent Temp. / °C Yield / % er

1 223 Et2O −78 71 50:50

2 224 Et2O −78 77 78:22

3 224 Et2O −100 41 79:21

4 224 Et2O-pentane −78 51 74:26

5 224 t-BuOMe −78 63 72:28

6 224 THF −78 81 59:41

7 233 Et2O −78 43 71:29

Further attempts to optimise this reaction were unsuccessful: neither lower temperature

(entry 3) nor different solvents (entries 4-6) improved the enantioselectivity. When

nosylate 233 was lithiated under the same conditions used for tosylate 224, bicycle

(R,R)-229 was formed in 43% yield and 71:29 er (entry 7).

In 2002, Beak and co-workers reported the lithiation-cyclisation of tosylate 224 under

the same conditions as was previously reported (2.2 eq. s-BuLi/(−)-sparteine, Et2O, −78

°C, 4 hours). Although trapping with trimethylsilyl chloride gave bicycle (R,R)-229 in

comparable enantioselectivity (75:25 er), the yield reported was vastly reduced (26%).41

No explanation for the difference between this result and that shown in Table 3.3, entry


98

2 (78% yield and 78:22 er) was provided. In this work, the absolute configuration of

the major enantiomer, (R,R)-229, was established by X-ray crystallography of the p-

bromobenzamide derivative.

3.4.2 s-BuLi/TMEDA-Mediated Lithiation of N-Boc 4-Chloro Piperidine and

Trapping with Andersen’s Sulfinate

We began our investigation with the racemic lithiation of N-Boc 4-chloro piperidine

223 using conditions reported by Beak et al. (2.2 eq. s-BuLi/TMEDA, Et2O, −78 °C, 6

hours178

) and electrophilic trapping with sulfinate 121. This gave sulfoxides syn-rac-

225 and anti-rac-225 in 35% and 36% yield respectively (Scheme 3.41, Table 3.4, entry

1). Our design had worked; we had successfully isolated a cyclic N-Boc α-amino

sulfoxide. The assignment of the stereochemistry of the diastereomeric sulfoxides was

made from the products of asymmetric lithiation which are presented later. Crucially,

the diastereomeric sulfoxides were readily separated by flash column chromatography

and had distinctive 1H and

13C NMR spectra. In addition, each diastereoisomer was

separable into a 50:50 mix of enantiomers by CSP-HPLC.

1. 2.2 eq. s-BuLiConditions

2.S

O

223 syn-rac-225 ant i-rac-225

NBoc

Cl

NBoc

S

O

NBoc

SOMe

O

121

Scheme 3.41

Table 3.4: Optimisation of the racemic lithiation of 4-chloro piperidine 223 and trapping

with sulfinate 121

Entry Conditions Yield of

syn-rac-225 / %

Yield of

anti-rac-225 / %

1 TMEDA, Et2O, −78 °C, 6 h 35 36

2 TMEDA, Et2O, −78 °C, 1 h 34 35

3 THF, −78 °C, 1 h 33 32

4 THF, −30 °C, 5 min 21 18


99

A reduction in lithiation time from 6 hours to 1 hour showed no reduction in yield, with

syn-rac-225 and anti-rac-225 being isolated in 34% and 35% yield respectively (entry

2). This indicated that significant lithiation occurred within 1 hour. A diamine-free

lithiation146

(s-BuLi/THF, 1 hour) at −78 °C gave both diastereoisomers in good yields

(entry 3). In contrast, repeating the lithiation at −30 °C for 5 minutes (conditions that

had previously been optimised by our group for the lithiation of a number of N-Boc

heterocycles)146

gave sulfoxide syn-rac-225 in 21% yield and sulfoxide anti-rac-225 in

18% yield (entry 4).

The difference in reactivity between N-Boc piperidine 48 and N-Boc 4-chloro piperidine

223 towards α-lithiation is remarkable. ReactIRTM

spectroscopic data recorded within

our group suggests that full lithiation of N-Boc piperidine 48 with s-BuLi/TMEDA

takes in excess of 90 minutes. 180

However, lithiation of N-Boc 4-chloro piperidine 223

under the same conditions required only 2 minutes for complete lithiation. In addition,

the reactivity difference is also apparent in isolated yields. It has been reported that the

s-BuLi/THF complex is unable to lithiate N-Boc piperidine146

whereas our results show

that the diamine-free lithiation of N-Boc 4-chloro piperidine 223 gives significant yields

at −78 °C (65% yield, Table 3.4, entry 3).

We postulate that the reactivity difference between N-Boc piperidine 48 and N-Boc 4-

chloro piperidine 223 arises due to an overlap between the back lobe of the C-H σ-

bonding orbital and the C-Cl σ* antibonding orbital. This would cause a weakening of

the C-H bond, effectively making the proton more acidic. Therefore, deprotonation is

more facile in N-Boc 4-chloro piperidine 223 than in N-Boc piperidine 48, where this

interaction does not exist (Figure 3.7).

Figure 3.7

Our attention then turned to the enantioselective synthesis of sulfoxides syn-(R,R,SS)-

225 and anti-(S,S,SS)-225. First, the racemic lithiation (2.2 eq. s-BuLi/TMEDA, Et2O,

−78 °C, 1 hour) of N-Boc 4-chloro piperidine 223 and trapping with 2.2 eq. Andersen’s


100

sulfinate (SS)-97 was investigated because we were concerned about a similar loss of

enantiomeric ratio during the trapping procedure as was observed in the case of O-alkyl

carbamate 14 (see Scheme 2.13). In fact, the reduction in enantiomeric ratio was even

more dramatic. Sulfoxide syn-(R,R,SS)-225 was isolated in 38% yield but only 58:42 er

and sulfoxide anti-(S,S,SS)-225 was isolated in 45% yield and 70:30 er (Scheme 3.42).

1. 2.2 eq. s-BuLi/TMEDA

Et2O, _78 °C, 1 h

2.S

O

223 SO

O

(SS)-97

syn-(R,R,SS)-225

38%, 58:42 eranti-(S,S,SS)-225

45%, 70:30 er

NBoc

Cl

NBoc

S

O

NBoc

Scheme 3.42

We postulate that the loss of enantiomeric ratio in the sulfoxide products occurs via a

similar process to that identified for α-alkoxy sulfoxides (see Scheme 2.14). Lithiation-

cyclisation of N-Boc 4-chloro piperidine 223 using s-BuLi/TMEDA will generate a

50:50 mixture of organolithium reagents (R,R)-228 and (S,S)-228. As an example,

trapping of (R,R)-228 with Andersen’s sulfinate (SS)-97 would give sulfoxide syn-

(R,R,SS)-225. As the amount of syn-(R,R,SS)-225 increases, competitive sulfoxide →

lithium exchange occurs mediated by (R,R)-228 as shown in Scheme 3.43. This would

give sulfoxide anti-(R,R,RS)-225. An analogous process by sulfoxide anti-(S,S,SS)-225

and organolithium (S,S)-228 would form sulfoxide syn-(S,S,RS)-225. It is in this manner

that the enantiomers of the expected major products, sulfoxides syn-(R,R,SS)-225 and

anti-(S,S,SS)-225 are formed. Hence a loss of enantiomeric ratio in the products is

observed. In addition, we suggest that organolithium reagents (R,R)-228 and (S,S)-228

are better leaving groups than lithiated O-alkyl carbamate, thus a greater loss of

enantiomeric ratio is observed in this system.


101

S

O

syn-(R,R,SS)-225

anti-(S,S,SS)-225

NBoc

S

O

NBoc

S

O

syn-(S,S,RS)-225

anti-(R,R,RS)-225

NBoc

S

O

NBoc

BocNLi

BocNLi

(R,R)-228

(S,S)-228

NBoc

Li

NBoc

Li

(R,R)-228

(S,S)-228

+

+

Scheme 3.43

Fortunately, the enantioselectivity was improved by modifying the procedure in a

similar fashion to that observed for the lithiation-trapping of O-alkyl carbamate 14

(Scheme 3.44, Table 3.5).

1. 2.2 eq. s-BuLi/TMEDA

Et2O, _78 °C, 1 h

2.S

O

223 SO

O

(SS)-97

syn-(R,R,SS)-225 anti-(S,S,SS)-225

NBoc

Cl

NBoc

S

O

NBoc

Scheme 3.44

Table 3.5: Optimisation of the racemic lithiation of N-Boc 4-choro piperidine 223 and

trapping with Andersen’s sulfinate (SS)-97.

Entry Reverse

Addition?

Length of Trap

at −78 °C / min

syn-(R,R,Ss)-225 anti-(S,S,Ss)-225


a

1 No 16 h b 38 58:42 45 70:30

2 No 5 36 80:20 47 78:22

3 Yes 5 39 89:11 44 88:12

4c Yes 5 41 90:10 43 91:9


bWarmed from −78 °C to rt,

c3.0 eq. of Andersen’s

sulfinate (SS)-97 used.


102

Indeed, we found that quenching the reaction after 5 minutes at −78 °C gave syn-

(R,R,SS)-225 in 36% yield and 80:20 er and anti-(S,S,SS)-225 in 47% yield and 78:22 er

(entry 2). This was a significant improvement compared to allowing the electrophilic

trapping warm to room temperature overnight (entry 1). Next, a reverse addition

protocol further improved the enantioselectivity to 89:11 er and 88:12 er for syn-

(R,R,SS)-225 and anti-(S,S,SS)-225 respectively (entry 3). Increasing the amount of

Andersen’s sulfinate (SS)-97 to 3.0 eq. did not further improve the enantiomeric ratio of

the products (entry 4).

To conclude, we were able to improve the enantiomeric ratio in the lithiation of N-Boc

4-chloro piperidine 223 and trapping with Andersen’s sulfinate (SS)-97 by using a

reverse addition protocol. Unfortunately, a significant loss of enantiomeric ratio during

the trapping process was still observed and therefore sulfoxides syn-(R,R,SS)-225 and

anti-(S,S,SS)-225 were not isolated in ≥99:1 er.

3.4.3 s-BuLi/Chiral Diamine-Mediated Lithiation of N-Boc 4-Chloro Piperidine

and Trapping with Andersen’s Sulfinate

Previously, we successfully carried out a chiral amplification during the asymmetric

lithiation of O-alkyl carbamate 14 and trapping with Andersen’s sulfinate (SS)-97 (see

Scheme 2.23). A similar strategy was envisaged for the synthesis of sulfoxides syn-

(R,R,SS)-225 and anti-(S,S,SS)-225. Therefore, our next step would be to introduce an

asymmetric lithiation followed by trapping with Andersen’s sulfinate (SS)-97 to give the

α-amino sulfoxides in 99:1 er.

Since Beak and co-workers reported that the leaving group has a dramatic effect on the

enantioselectivity of the lithiation-trapping procedure, we envisaged that using 4-

sulfonyl derivatives would give products in good enantiomeric ratio. Consequently, we

investigated the asymmetric lithiation of 4-substituted piperidines 223 (4-Cl), 224 (4-

OTs) and 234 (4-OSO2Ar, Ar = 2,4,6-triisopropylbenzene) with s-BuLi/(−)-sparteine

(Et2O, −78 °C, 1 hour) and subsequent electrophilic trapping with phenylisocyanate

(Scheme 3.45, Table 3.6). Lithiation of N-Boc 4-chloro piperidine 223 with s-BuLi/(−)-

sparteine and electrophilic trapping with phenylisocyanate gave amide (S,R)-235 in 94%

yield but low enantiomeric ratio (56:44 er) (entry 1). The low enantioselectivity was


103

unsurprising as Beak had previously shown that lithiation-trapping of N-Boc 4-chloro

piperidine 223 gave racemic products.172


Et2O, _78 °C, 1 h

2. PhNCO

HN

(S,R)-235

NBoc

X

NBoc

O

Ph

223, X = Cl224, X = OTs234, X = OSO2Ar

Ar =

Scheme 3.45

Table 3.6: Asymmetric lithiation of 4-subsituted piperidines 223, 224 and 234 and

trapping with phenyl isocyanate

Entry Starting Material Yield / % era

1 223 94 56:44

2 224 -b -

3 234 84 58:42


bStarting tosylate 224 was recovered in 92% yield.

Then, we attempted the enantioselective lithiation-trapping of N-Boc 4-tosyloxy

piperidine 224. However, none of the expected amide (S,R)-235 was isolated and

starting tosylate 224 was recovered in 92% yield (entry 2). This result is consistent

across a number of repeats, and we have been unable to successfully lithiate and trap N-

Boc 4-tosyloxy piperidine 224. Our result is clearly at odds with those reported by

Beak (see Table 3.3, entry 2). It is possible that N-Boc 4-tosyloxy piperidine 224

undergoes ortho-lithiation but is not trapped by the electrophile and therefore

reprotonated on work-up. As an alternative to N-Boc 4-tosyloxy piperidine 224, N-Boc

4-sulfonyl piperidine 234 was lithiated with s-BuLi/(−)-sparteine. This substrate cannot

undergo ortho-lithiation. Subsequent trapping with phenylisocyanate gave amide (S,R)-

235 in good yield (84%) but in only 58:42 er (entry 3). In contrast to Beak’s

observations, we did not see a significant improvement in enantioselectivity of the

lithiation-trapping when changing the leaving group. Unfortunately, such low

enantioselectivity for the lithiation-trapping would not provide significant benefits for

our chiral amplification protocol.


104

A higher enantioselectivity was required and so a new approach was considered. We

postulated that a kinetic resolution of azabicycle 227 could be carried out to give amide

(S,R)-235 in high enantioselectivity. This would require one enantiomer of rac-227 to

be deprotonated faster than the other enantiomer when using 0.5 eq. of a chiral base.

The required substrate was prepared by lithiation of N-Boc 4-chloro piperidine 223 with

s-BuLi/TMEDA and quenching with methanol to furnish azabicycle rac-227 in 87%

yield (Scheme 3.46).

1. s-BuLi, TMEDA

Et2O, _78 °C, 1 h

2. MeOH

rac-227, 87%

NBoc

Cl

NBoc

223

H

Scheme 3.46

Kinetic resolution of azabicycle rac-227 was then attempted by deprotonation with 0.5

eq. of a chiral base in Et2O at −78 °C for 1 hour (Scheme 3.47, Table 3.7).

Deprotonation with s-BuLi/(−)-sparteine and trapping with phenylisocyanate gave

amide (R,S)-235 in 36% yield and 56:44 er (entry 1). Azabicycle (R,S)-227 was also

isolated in 30% yield and was presumed to be in improved enantiomeric ratio but this

has not been determined

1. 0.5 eq. Base, Et2O_78 °C, 1 h

2. PhNCO

rac-227

NBoc

NBoc

O

HN

Ph

(S,R)-235

NBoc

(R,S)-227

NH

(S)-236

H

Scheme 3.47

Table 3.7: Kinetic resolution of rac-227

Entry Base

(S,R)-235 (R,S)-227


a

1 s-BuLi/(−)-sparteine 36 56:44 30 nd

2 n-BuLi/(−)-sparteine 44 56:44 52 nd

3 n-BuLi/(S)-236b - - 91 nd

aer determined by CSP-HPLC, nd – not determined,

breaction carried out in THF


105

We hypothesised that due to the acidity of the cyclopropyl proton in rac-227, s-

BuLi/(−)-sparteine was such a strong base that both enantiomers of azabicycle rac-227

react at a similar rate under the reaction conditions leading to a trapped product with

low enantiomeric ratio. By using the less basic n-BuLi/(−)-sparteine we hoped that we

would see an improvement in enantioselectivity during the kinetic resolution.

Unfortunately, amide (S,R)-235 was isolated in 44% yield and only 56:44 er from this

reaction (entry 2). The pKa of the base was further reduced by using n-BuLi/(S)-227 in

THF, which is reported to act as a chiral LDA equivalent.181

However, treatment of

azabicycle rac-227 with n-BuLi/(S)-236 did not lead to the formation of the desired

amide (S,R)-235 and the starting material was recovered in 91% yield (entry 3). The

high recovery of rac-227 suggests that the lithium amide base was not strong enough

deprotonate the cyclopropyl proton.

Undeterred, we hoped that changing the ligand used in the asymmetric lithiation of N-

Boc 4-chloro piperidine 223 would have a positive influence on the enantioselectivity of

the reaction (Scheme 3.48, Table 3.8). Lithiation of N-Boc 4-chloro piperidine 223 by

s-BuLi/(+)-sparteine surrogate 1 and trapping with phenylisocyanate gave amide (R,S)-

235 in good yield (79%) but low enantiomeric ratio (54:46 er) (entry 2). When the

deprotonation was mediated by s-BuLi/(S,S)-42, amide (R,S)-235 was isolated in 74%

yield and an improved 67:33 er (entry 3). Finally, lithiation of N-Boc 4-chloro

piperidine 223 using (R,R)-237182

as a ligand and trapping with phenylisocyanate gave

amide (S,R)-235 in 81% yield and 62:38 er (entry 4).

1. s-BuLi, ligand

Et2O, _78 °C, 1 h

2. PhNCO

HN

(S,R)-235

NBoc

Cl

NBoc

O

Ph

223

MeN

NMe

tButBu

(S,S)-42

Ph

MeN

NMe

tButBu

(R,R)-237

N N

N NH

H

H

(_)-sparteine (+)-sparteinesurrogate 1

HN

(R,S)-235

NBoc

O

Ph

Scheme 3.48


106

Table 3.8: Asymmetric lithiation of N-Boc 4-chloro piperidine 223 using s-BuLi/chiral

ligands and trapping with phenyl isocyanate

Entry Ligand Yield / % er (S,R):(R,S)a

1 (−)-sparteine 94 56:44

2 (+)-sparteine surrogate 1 79 46:54

3 (S,S)-42 74 33:67

4 (R,R)-237 81 62:38

aer determined by CSP-HPLC

The lithiation of N-Boc 4-chloro piperidine 223 with s-BuLi/(S,S)-42 gave the highest

enantioselectivity that we have been able to achieve (67:33 er). However, we were

uncertain if this would be significant enough in the chiral amplification protocol to give

α-amino sulfoxides in ≥99:1 er. To investigate this, we repeated the lithiation under the

same conditions and trapped with Andersen’s sulfinate (SS)-97 using the reverse

addition procedure (Scheme 3.49). From the reaction, sulfoxide syn-(R,R,Ss)-225 was

isolated in 12% yield and 89:11 er and sulfoxide anti-(S,S,Rs)-225 was isolated in 54%

yield and 87:13 er. Disappointingly, neither diastereoisomer was isolated in 99:1 er.

1. s-BuLi, (S,S)-42

Et2O, _78 °C, 1 h

2.S

O

223 SO

O

(SS)-97

syn-(R,R,Ss)-225

12%, 89:11 eranti-(S,S,Ss)-225

54%, 87:13 er

NBoc

Cl

NBoc

S

O

NBoc

Reverse Addition

MeN

NMe

tButBu

(S,S)-42

Scheme 3.49

The enantioselective lithiation and trapping with Andersen’s sulfinate (SS)-97 allows

assignment of the absolute configuration of the diastereomeric sulfoxides. Lithiation of

N-Boc 4-chloro piperidine 223 with s-BuLi/(S,S)-42 is believed to give organolithium

reagents (S,S)-226 and (R,R)-226 in 67:33 er which immediately cyclises to give (R,S)-

227 and (S,R)-227 in 67:33 er (Scheme 3.50). Lithiation of piperidines by s-BuLi/(S,S)-

42 has been shown to occur with opposite enantioselectivity to s-BuLi/(−)-sparteine.42

Therefore we are able to compare our result with that reported in the literature for the


107

lithiation of N-Boc 4-tosyloxy piperidine 224 by s-BuLi/(−)-sparteine to confirm the

stereochemistry of (R,S)-227 and (S,R)-227.41,172

Subsequent lithiation of (R,S)-227 and

trapping with inversion113

of Andersen’s sulfinate (SS)-97 would give sulfoxide anti-

(S,S,Ss)-225 as the major diastereoisomer.

s-BuLi, (S,S)-42

1. s-BuLi, (S,S)-42

2. Andersen's

Sulfinate (SS)-97

S

O

223

SO

O

(S,S)-226


NBoc

Cl

NBoc

S

O

NBoc

NBoc

NBoc

H H

NBoc

Cl

NBoc

Cl

Et2O, _78 °C, 1 hLi Li

(R,R)-226

(S,R)-227 (R,S)-227

33:67

33:67

'minor ' 'major'

(SS)-97

Scheme 3.50

We believed there were two possible reasons for our inability to synthesise the major

diastereomeric sulfoxide anti-(S,S,Ss)-225 in 99:1 er. First, we thought that the poor

enantioselectivity of the initial lithiation reaction was causing a reduction in

enantiomeric ratio of the trapped products. Second, there may be a match-mismatch

effect caused by the chiral lithiated intermediate reacting with a chiral electrophile.

Our initial efforts focused upon improving the enantioselectivity of the lithiation-

cyclisation of N-Boc 4-chloro piperidine 223. In 2007, the groups of Coldham and

O’Brien reported that the enantioselectivity of lithiation of N-Boc 4-phenyl piperidine

238 was improved when using 0.65 eq. of s-BuLi.42

It was suggested that N-Boc 4-

phenyl piperidine 238 exists as two rotameric species in solution at −78 °C and ring-


108

flipping is not thought to occur at this temperature due to the substituent at C4.

Furthermore, it is well established in the literature that during the lithiation of N-Boc

heterocycles only the equatorial proton is removed.41,148

Therefore, when effecting a

deprotonation using s-BuLi and chiral diamines we see a ‘matched’ rotamer and a

‘mismatched’ rotamer. An example of this is shown in Scheme 3.51. Deprotonation of

N-Boc 4-phenyl piperidine 238 with 1.3 eq. of s-BuLi/diamine (S)-240 gave silyl

piperidine (S,S)-239 in 68% yield and 58:42 er. An improvement in enantioselectivity

was observed when using 0.65 eq. of s-BuLi/diamine (S)-240 with silyl piperidine (S,S)-

239 being isolated in 24% yield and 63:37 er. Although the increase in enantiomeric

ratio is not large, it provides evidence that there is no rotation of the N-Boc group at −78

°C.

1. 1.3 eq. s-BuLi, (S)-240

Et2O, _78 °C, 1 h

2. Me3SiCl

(S,S)-23968%, 58:42 er

NBoc

Ph

238

NBoc

Ph

SiMe3

1. 0.65 eq. s-BuLi, (S)-240

Et2O, _78 °C, 1 h

2. Me3SiCl

(S,S)-23924%, 63:37 er

NBoc

Ph

238

NBoc

Ph

SiMe3

Me2N NMe2

Ph

(S)-240

Scheme 3.51

We hoped that a similar type of kinetic resolution could be carried out for the

deprotonation of N-Boc 4-chloro and 4-sulfonyl piperidines 223 and 234. Therefore,

piperidines 223 and 234 were treated with 1.1 eq. of s-BuLi/chiral diamine at −78 °C

and trapped with phenylisocyanate (Scheme 3.52). One equivalent of s-BuLi will

deprotonate the piperidine and the second will deprotonate the intermediate cyclopropyl

proton. The results for lithiation with 2.2 eq. and 1.1 eq. s-BuLi/chiral diamine are

summarised in Table 3.9.

Overall, no improvement in enantiomeric ratio was observed when reducing the amount

of s-BuLi/chiral diamine to 1.1 eq. when compared with results obtained with 2.2 eq. of

s-BuLi/chiral diamine. This is highlighted with the lithiation of N-Boc 4-chloro


109

piperidine 223 with s-BuLi/(−)-sparteine and trapping with phenylisocyanate which

gave amide (S,R)-235 in 45% yield and 56:44 er (entry 1). This is the same

enantiomeric ratio as the product isolated previously (entry 2). A similar result was

observed with N-Boc 4-sulfonyl piperidine 234 (entries 3 and 4).

1. n eq. s-BuLi, diamine

Et2O, _78 °C, 1 h

2. PhNCONBoc

X

NBoc

O

NHPh

(S,R)-235223, X=Cl

234, X=OSO2Ar

Ar =

Scheme 3.52

Table 3.9: Kinetic resolution of 4-substituted piperidines 223 and 234

Entry n Starting Material Diamine Yield / % er (S,R):(R,S)a

1 1.1 223 (−)-sparteine 45 56:44

2 2.2 223 (−)-sparteine 93 56:44

3 1.1 234 (−)-sparteine 42 58:42

4 2.2 234 (−)-sparteine 84 58:42

5 1.1 223 (S,S)-42 43 43:57

6 2.2 223 (S,S)-42 74 33:67


When effecting the kinetic resolution of N-Boc 4-chloro piperidine 223 using s-

BuLi/(S,S)-42, amide (R,S)-235 was isolated in 43% yield and 57:43 er (entry 5). The

reduction in enantiomeric ratio when compared to the standard reaction (67:33 er, entry

6) is likely to be due to the capricious nature of the lithiation reaction.

Later, it was postulated that by increasing the temperature of the lithiation step the

rotamers may be able to freely interconvert around the N-CO bond. This could allow

the matched rotamer to be lithiated in both high yield and higher enantiomeric ratio than

the 67:33 er which is exhibited at −78 °C. Therefore, 4-substituted piperidines 223 and

234 were deprotonated with s-BuLi/(S,S)-42 at −40 and −30 °C (Scheme 3.53 and Table

3.10). First, N-Boc 4-chloro piperidine 223 was lithiated with s-BuLi/(S,S)-42 at −30

°C for 5 minutes and trapping with phenylisocyanate to give amide (R,S)-235 in 52:48


110

er (entry 2). Disappointingly, there was a reduction in enantiomeric ratio when

compared to the product of the lithiation-trapping at −78 °C (67:33 er, entry 1).

1. s-BuLi, (S,S)-42

Et2O, temp., time

2. PhNCONBoc

X

NBoc

O

NHPh

(R,S)-235223, X=Cl234, X=OSO2Ar

Ar =

Scheme 3.53

Table 3.10: Investigating the temperature effect on the lithiation-cyclisation of 4-

subsituted piperidine 223 and 234

Entry Starting

Material Temp. / °C Time / min Yield / % er

a

1 223 −78 60 74 67:33

2 223 −30 5 74 52:48

3 223 −40 60 69 67:33

4 234 −40 60 73 58:42


By lowering the temperature of lithiation to −40 °C, amide (R,S)-235 was isolated in

69% yield and 67:33 er (entry 3). However, this is not an improvement upon the

enantiomeric ratio observed at −78 °C. Finally, lithiation of N-Boc 4-sulfonyl

piperidine 234 at −40 °C and trapping with phenylisocyanate gave amide (R,S)-235 in

73% yield and 58:42 er (entry 4). From these results we could conclude that changing

the temperature does not have a significant effect on the enantioselectivity of the

reaction.

In an attempt to improve the control of the reaction conditions, we added s-BuLi to 223

and 234 via syringe pump over 30 minutes (Scheme 3.54, Table 3.11). Unfortunately,

no improvement in enantiomeric ratio was seen. Lithiation of N-Boc 4 chloro

piperidine 223 with s-BuLi/(S,S)-42 at −78 °C gave amide (R,S)-235 in 53% yield and

59:41 er (entry 1). However at −40 °C, amide (R,S)-235 was isolated in 69% yield and

67:33 er (entry 2). Whilst the enantiomeric ratio was better at −40 °C, it is still


111

comparable to that which can be obtained through the standard lithiation-trapping

procedure.

1. s-BuLi, (S,S)-42

Et2O, temp., time

2. PhNCONBoc

X

NBoc

O

NHPh

(R,S)-235223, X=Cl234, X=OSO2Ar

Ar =

s-BuLi added toSM/Ligand

Scheme 3.54

Table 3.11: Lithiation of 4-substituted piperidines 223 and 234 with slow addition of s-

BuLi and trapping with phenyl isocyanate

Entry Starting Material Temp. / °C Yield / % era

1 223 −78 53 59:41

2 223 −40 69 67:33

3 234 −78 76 57:43

4 234 −40 98 58:42


In a similar fashion, we added a solution of 4-substitued piperidines 223 and 234 via

syringe pump over 30 minutes to a stirred solution of s-BuLi/chiral diamines (Scheme

3.55 and Table 3.12). No improvement in enantiomeric ratio was observed at −78 °C or

−40 °C. Indeed, when (S,S)-42 was used as a ligand, amide (R,S)-235 was isolated in

62:38 er at −78 °C (entry 1) and 60:40 er at −40 °C (entry 2). Furthermore, changing

the ligand to (−)-sparteine led to amide (S,R)-235 being isolated in 54:46 er at −78 °C

(entry 3) and 58:42 er at −40 °C (entry 4).

1. s-BuLi, LigandEt2O, temp., time

2. PhNCONBoc

X

NBoc

O

NHPh

(S,R)-235223, X=Cl234, X=OSO2Ar

SM added tos-BuLi/Ligand

Ar =

Scheme 3.55


112

Table 3.12: Lithiation-of 4-substituted piperidines 223 and 234 with slow addition of

starting material and trapping with phenyl isocyanate

Entry Starting

Material Ligand Temp. / °C Yield / % er (S,R):(R,S)

a

1 223 (S,S)-42 −78 70 38:62

2 223 (S,S)-42 −40 71 40:60

3 223 (−)-sparteine −78 68 54:46

4 223 (−)-sparteine −40 73 58:42

5 234 (−)-sparteine −78 99 56:44


Due to the apparently facile lithiation of N-Boc 4-chloro piperidine 223 using s-

BuLi/(−)-sparteine, we postulated that the deprotonation may be effected with n-BuLi.

Thus, N-Boc 4-chloro piperidine 223 was treated with 2.2 eq. n-BuLi/(−)-sparteine

followed by addition of phenylisocyanate (Scheme 3.56). Unfortunately, amide (S,R)-

235 was not evident in the 1H NMR spectrum of the crude product and N-Boc 4-chloro

piperidine 223 was recovered in 97% yield.

1. n-BuLi, (_)-sparteine

Et2O, _78 °C, 1 h

2. PhNCONBoc

Cl

NBoc

O

NHPh

(S,R)-235, 0%223

+ 97% RSM

Scheme 3.56

To summarise, it was not possible to improve the enantioselectivity in the lithiation-

trapping of N-Boc 4-chloro piperidine 223 and N-Boc 4-sulfonyl piperidine 234. We

have also been unable to reproduce Beak’s result with s-BuLi/(−)-sparteine and N-Boc

4-tosyloxy piperidine 224. The best enantiomeric ratio achieved so far has been for the

lithiation of N-Boc 4-chloro piperidine 223 mediated by s-BuLi/(S,S)-42 and trapping

with phenyl isocyanate (67:33 er).

Next, we wanted to investigate any match/mismatch effect between the chiral lithiated

intermediates and Andersen’s sulfinate (SS)-97. The lithiation of N-Boc 4-chloro


113

piperidine 223 using s-BuLi/(S,S)-42 and trapping with Andersen’s sulfinate (SS)-97 had

previously given disappointing enantioselectivity: sulfoxides syn-(R,R,Ss)-225 and anti-

(S,S,Rs)-225 were isolated in 89:11 er and 87:13 er respectively (see Scheme 3.49).

Therefore, we wanted to carry out the “diastereomeric reaction” mediated by s-

BuLi/(R,R)-42 and trapping with the same enantiomer of Andersen’s sulfinate (SS)-97.

To our delight, we were able to isolate sulfoxide syn-(R,R,Ss)-225 in 51% yield and 99:1

er together with anti-(S,S,Rs)-225 in 25% yield and 87:13 er (Scheme 3.57).

1. s-BuLi, (R,R)-42

Et2O, _78 °C, 1 h

2.S

O

223 SO

O

(SS)-97

syn-(R,R,Ss)-225

51%, 99:1 eranti-(S,S,Ss)-225

25%, 87:13 er

NBoc

Cl

NBoc

S

O

NBoc

Reverse Addition

MeN

NMe

tButBu

(R,R)-42

Scheme 3.57

To understand this match/mismatch effect, the mechanism which accounts for the

reduction of enantiomeric ratio of the products needs to be considered. As we have

previously shown for O-alkyl carbamate 14 (see Scheme 2.17), a reduction in

enantiomeric ratio is caused by attack of the lithiated intermediate on the forming

sulfoxide products causing a second inversion at sulfur to take place. Based on the

inherent enantioselectivity of this reaction (67:33 er determined by lithiation-trapping

with phenylisocyanate, see Scheme 3.48), lithiation-cyclisation of N-Boc 4-chloro

piperidine 223 mediated by s-BuLi/(R,R)-42 will give diastereomeric lithiated

intermediates 228 in a 67:33 ratio (Scheme 3.58). The lithiated intermediates are then

trapped by Andersen’s sulfinate (SS)-97 with inversion at sulfur to give sulfoxides syn-

(R,R,SS)-225 and anti-(S,S,RS)-225. Due to the electrophilicity of these products, the

lithiated intermediates 228 and 228 can attack the sulfoxide moiety, with inversion at

sulfur, to give enantiomeric sulfoxides syn-(S,S,RS)-225 and anti-(R,R,SS)-225.


114

s-BuLi, (R,R)-42

Andersen's

Sulfinate (Ss)-97

S

O

223

SO

O

(SS)-97


NBoc

Cl

NBoc

S

O

NBoc

MeN

NMe

tButBu

(R,R)-42

NBoc

NBoc

Li.(R,R)-42 Li.(R,R)-42Et2O, _78 °C, 1 h

228 228

NBoc

Li.(R,R)-42NBoc

Li.(R,R)-42

S

O

NBoc

S

O

NBoc

syn-(S,S,Rs)-225 anti-(R,R,Rs)-225

228 228

Scheme 3.58

When the enantiomeric ligand (S,S)-42 is used for the lithiation-trapping process, a

“diastereomeric reaction” occurs. For example, consider the minor lithiated species in

the reaction with the major sulfoxide product formed in each case (Scheme 3.59). For

the lithiation mediated by s-BuLi/(R,R)-42, lithiated intermediate 228 reacts with

sulfoxide syn-(R,R,SS)-225 slowly to give sulfoxide syn-(S,S,RS)-225. When the

lithiation is mediated by (S,S)-42 the minor lithiated intermediate is now ent-228 which

quickly reacts with sulfoxide anti-(S,S,SS)-225 to give anti-(R,R,RS)-225. The key

difference is that the major sulfoxides formed in each reaction have the same

configuration at sulfur, but the lithiated intermediates are enantiomeric. This gives rise

to diastereomeric transition states which result in differing rates of reaction.

Experimental evidence would suggest that the reaction of ent-228 with sulfoxide anti-

(S,S,SS)-225 is a more facile process. Thus, a greater loss of stereospecificity in the

trapping reaction is observed.


115

NBoc

Li.(R,R)-42

NBoc

Li.(R,R)-42

S

O

NBoc

S

O

NBoc

S

O

NBoc

S

O

NBoc

Fast

Slow

ent-228

228

anti-(R,R,RS)-225

syn-(S,S,RS)-225

anti-(S,S,SS)-225

syn-(R,R,SS)-225

Scheme 3.59

Finally, the lithiation was conducted using (−)-sparteine and (+)-sparteine surrogate 1

and then trapped with Andersen’s sulfinate (SS)-97 (Scheme 3.60). From the reaction

mediated by (−)-sparteine, sulfoxide syn-(R,R,SS)-225 was isolated in 27% yield and

96:4 er and sulfoxide anti-(S,S,SS)-225 was isolated in 24% yield and 89:11 er. Use of

(+)-sparteine surrogate 1 gave sulfoxide syn-(R,R,SS)-225 in 26% yield and 99:1 er and

sulfoxide anti-(S,S,SS)-225 in 27% yield and 93:7 er. To our surprise the predicted

minor diastereoisomer from this reaction gave the higher enantiomeric ratio. However,

we propose that this is because of a ‘matched’ effect similar to that observed with

diamine (R,R)-42. The poor diastereoselectivity in both of these reactions is due to the

poor enantioselectivity of the initial lithiation-cyclisation reaction (ca. 56:44 er, see

Scheme 3.49).

1. s-BuLi, diamine

Et2O, _78 °C, 1 h

2.S

O

223 SO

O

(SS)-97

(_)-sp: 27%, 96:4 er

1: 26%, 99:1 er

(_)-sp: 24%, 89:11 er

1: 27%, 93:7 er

NBoc

Cl

NBoc

S

O

NBoc

Reverse Addit ion

ant i-(S,S,Ss)-225syn-(R,R,Ss)-225

N

NH

H

(_)-sparteine

N

NH


Scheme 3.60

To conclude, we have been able to synthesise syn-(R,R,SS)-225 in 99:1 er by the

lithiation-trapping of N-Boc 4-chloro piperidine 223 with Andersen’s sulfinate (SS)-225.

Despite the low enantioselectivity (67:33 er) of the initial lithiation-cyclisation, we were


116

able to utilise a matched effect between diamine (R,R)-42 and Andersen’s sulfinate to

increase the stereochemical fidelity within the reaction. Unfortunately, diastereomeric

sulfoxide anti-(S,S,SS)-225 could not be synthesised in 99:1 er. This was due to a

mismatch effect between diamine (S,S)-42 and Andersen’s sulfinate (SS)-97 which

caused an erosion in enantiomeric ratio at sulfur within the trapping reaction. Sulfoxide

syn-(S,S,RS)-225 could be synthesised in 99:1 er by lithiation of N-Boc 4-chloro

piperidine 223 mediated by s-BuLi/(S,S)-42 and trapping with ent-Andersen’s sulfinate

(RS)-97. Enantiomeric sulfoxides syn-(R,R,SS)-225 and syn-(S,S,RS)-225 would then

allow access to α-amino Grignard reagents in both enantiomeric series via sulfoxide →

magnesium exchange. Significantly, we do not need to use (−)-sparteine to generate N-

Boc amino sulfoxide syn-(R,R,SS)-225 in 99:1 er.


117

3.5 Sulfoxide → Magnesium Exchange

Our next goal was to synthesise α-amino Grignard reagent (R,R)-240 in 99:1 er from

sulfoxide syn-(R,R,SS)-225. It was hoped that sulfoxide → magnesium exchange would

prove to be an efficient method of accessing a range of 2-subsitited products as single

enantiomers (Scheme 3.61).

S

O

NBoc

syn-(R,R,Ss)-225

MgClNBoc

i-PrMgCl

THF, rt, 1 min

E+

(R,R)-240

ENBoc

Scheme 3.61

3.5.1 Sulfoxide → Magnesium Exchange Reactions

We began our investigation by using sulfoxide → magnesium exchange conditions

previously optimised for α-alkoxy sulfoxides anti-(S,Ss)-103 and syn-(R,Ss)-103 (i-

PrMgCl, THF, rt, 1 min, see Scheme 2.26, Table 2.3). Thus, sulfoxide syn-(R,R,SS)-225

was treated with i-PrMgCl to form Grignard reagent (R,R)-240 and then electrophiles

were added (Scheme 3.62). Trapping with methyl chloroformate gave ester (S,R)-241

in 89% yield and 99:1 er and trapping with phenylisocyanate gave amide (S,R)-235 in

67% yield and 99:1 er. All racemic compounds were prepared from syn-rac-225 and

separated by CSP-HPLC

S

O

NBoc

syn-(R,R,Ss)-225

MgClNBoc

i-PrMgCl

THF, rt, 1 min

E+

(R,R)-240

NBoc

O

OMeNBoc

O

NHPh

(S,R)-241

89%, 99:1 er

E+= MeOCOCl

(S,R)-235

67%, 99:1 er

E+= PhCHO

Scheme 3.62

We also trapped Grignard reagent (R,R)-240 with allyl bromide and benzyl bromide

(Scheme 3.63). Use of catalytic CuBr.SMe2 in both cases gave access to alkene (S,R)-


118

230 and (R,R)-242 respectively, with both being isolated in good yields and 99:1 er. If

CuBr.SMe2 is absent from the trapping procedure then lower yields are observed.

S

O

NBoc

syn-(R,R,Ss)-225

MgClNBoc

i-PrMgCl

THF, rt, 1 min

E+

(R,R)-240

NBoc

NBoc

Ph

(S,R)-230

69%, 99:1 er

E+= Allyl-Br

(S,R)-242

64%, 99:1 er

E+= BnBr

10 mol%CuBr.SMe2

Scheme 3.63

Grignard reagent (R,R)-240, formed by sulfoxide → magnesium exchange from syn-

(R,R,SS)-225, was also coupled to aryl bromides (Scheme 3.64). This process proceeds

via transmetallation to zinc and palladium-mediated Negishi coupling in similar fashion

to that developed for α-lithiated N-Boc pyrrolidine by Campos and co-workers.39,40

In

this way, a series of arylated heterocycles (S,R)-243-246 were generated in good yields

and 99:1 er. During the course of this thesis, Bull et al. reported a similar

transmetallation-Negishi reaction of Grignard reagents formed by sulfoxide →

magnesium exchange (see Scheme 1.46).98

S

O

NBoc

syn-(R,R,Ss)-225

MgClNBoc

i-PrMgCl

THF, rt, 1 min ArNBoc

1. ZnCl2, rt, 30 min

(R,R)-240

NBoc

NBoc

NBoc

NBoc

(S,R)-24368%, 99:1 er

(S,R)-24468%, 99:1 er

(S,R)-24574%, 99:1 er

(S,R)-24672%, 99:1 er

2. 5 mol% Pd(OAc)2

6 mol% tBuPHBF4

ArBr, rt, 16 h

S

OMe CO2Me

Scheme 3.64

3.5.2 Proof of Stereochemistry and Formal Synthesis of Saxagliptin

We wanted to prove the absolute stereochemistry of sulfoxide syn-(R,R,SS)-225. A

number of attempts to grow crystals of sulfoxides syn-(R,R,SS)-225 and anti-(S,SS)-225

for X-ray diffraction proved unsuccessful. In addition, endeavours were made to

synthesise a number of derivatives of syn-(R,R,SS)-225 (Scheme 3.65). Unfortunately,


119

the syntheses of nitrobenzylamine 247 and p-bromobenzamide 248 were unsuccessful

and all attempts to grow crystals of picrate salt 249 were fruitless.

S

O

NBoc

syn-(R,R,Ss)-225

S

O

N

O2N

S

O

NH2

O

NO2O2N

NO2

247

249

or

or

S

O

N

Br

O

248

Scheme 3.65

Therefore, we planned to convert sulfoxide syn-(R,R,SS)-225 into known alcohol cis-

253.183

Alcohols cis-253 and trans-253 are reported in the literature although no

characterisation data is available. However, Professor Hanessian kindly supplied full

data for each compound for comparison.184

In addition, synthesis of alcohol cis-253

would also constitute a formal synthesis of the oral hypoglycaemic drug,

saxagliptin.176,177,185

Saxagliptin was first developed by Bristol-Myers-Squibb in 2004

and later brought to market in collaboration with AstraZeneca under the brand name

Onglyza in 2009. The reported synthesis of saxagliptin concludes with a late-stage

amide coupling of commerically available amino acid (S)-251 to amine cis-250.177

Amine cis-250 was synthesised from N-Boc amide cis-252 via amide dehydration and

Boc deprotection.176

Finally, amide cis-252 can be synthesised in two steps from

alcohol cis-253 (Scheme 3.66).

OH

NNC

O

NH2

OH

OH

O

NH2

NH

NC NBoc

O

H2NNBoc

1. Oxidation2. Amidation

1. Dehydration2. DeprotectionAmidation

Saxagliptincis-252 cis-253

cis-250

(S)-251

NBoc

trans-253

OH

OH

+

Scheme 3.66


120

Our planned synthesis of alcohol cis-253 is shown in Scheme 3.67. It was envisaged

that the synthesis would begin by reduction of sulfoxide syn-(R,R,SS)-225 to give sulfide

(R,R)-254. The next step would be a diastereoselective lithiation-trapping with carbon

dioxide. It was hoped that the sulfide moiety would provide suitable protection of the

acidic cyclopropyl position. Moreover, if the substrate-controlled lithiation did not give

a cis-selective lithiation, a chiral ligand could be used to direct the lithiation to the

desired product.29

Then, reduction of the carboxylic acid would give alcohol cis-255

and reductive cleavage of the sulfide would complete the synthesis of alcohol cis-253.

SpTol

O

NBoc

syn-(R,R,Ss)-225

NBoc

SNBoc

S NBoc

1. s-BuLi

2. CO2

3. BH3.SMe2

ReductionReductiveCleavage

cis-253

pTol

OH

pTol

(R,R)-254 cis-255

OH

Scheme 3.67

First, we attempted the reduction of sulfoxide syn-(R,R,SS)-225. A number of

conditions were explored but they returned quantitative amounts of unreacted starting

material (RhCl(PPh3)3/catechol borane,186

or sodium borohydride/iodine187

) or a

complex mixture of unidentified products (BF3.Et2O/sodium iodide188

or triflic

anhydride/potassium iodide189

). To our delight, reduction of sulfoxide syn-(R,R,SS)-225

using trifluoroacetic anhydride/sodium iodide (acetone, −40 °C, 10 minutes190,191

) gave

sulfide (R,R)-254 in 99% yield (Scheme 3.68).

NBoc

SpTol

NBoc

SpTol

O

NaI, TFAA

acetone, _40 °C, 10 min

syn-(R,R,Ss)-225 (R,R)-254, 99%

Scheme 3.68

Next, we investigated the diastereoselective lithiation-trapping reaction. Beak and co-

workers have reported that α-lithiation of 2-substituted piperidines occurred in the 6-

position with almost exclusively trans-diastereoselectivity.148,192

This is due to the 2-

substituent preferably occupying an axial position in order to minimise steric interaction

with the Boc group. Thus, subsequent equatorial lithiation41,148

gives the trans-product.

Whilst this effect is not as prevalent in 2-subituted pyrrolidines,148

we postulated that a


121

similar situation could occur for the lithiation of (R,R)-254 due to configurational

constraints of the fused cyclopropyl ring (Scheme 3.69).

N

S

H

H

O

tBuO

SNBoc

N

S

Li

H

O

tBuO

s-BuLi, TMEDA

Equatorial Lithiat ion

(R,R)-254

Scheme 3.69

In addition, sulfide (R,R)-254 has the potential to exist in two rotameric forms (Figure

3.8). The Boc carbonyl group is known to direct the lithiation of N-Boc heterocycles22

and therefore in unsymmetrical systems the rotameric forms would give different

lithiation regioisomers. This phenomenon was observed in the lithiation of N-Boc 2-

phenyl pyrrolidine.193

In the case of sulfide (R,R)-254, rotamer A would be unreactive

as there are no α-protons whereas rotamer B would direct lithiation to the required α-

position. Therefore, a low yield in the lithiation-trapping of sulfide (R,R)-254 could be

indicative of slow interconversion of the rotameric species at −78 °C.

SN

(R,R)-254

Ot-BuO

SN

Ot -BuO

HH

H H

(R,R)-254

Unreactive Rotamer A Reactive Rotamer B

Figure 3.8

We began our investigation by undertaking the substrate-directed lithiation of sulfide

(R,R)-254 using s-BuLi/TMEDA in Et2O at −78 °C for 10 minutes. Trapping with

carbon dioxide and subsequent reduction of crude acid 256 with BH3.SMe2 gave alcohol

cis-255 in 65% yield and trans-255 in 26% yield (Scheme 3.70). The 1H NMR

spectrum of the crude intermediate acid 256 showed a moderate diastereoselectivity of

68:32 dr. Unfortunately, the diastereomeric ratio of alcohols cis-255 and trans-255

could not be calculated from the 1H NMR spectrum of the crude product due to

overlapping signals. The high yield from this reaction sequence (91% total yield over


122

two steps) indicates that sulfide (R,R)-254 either exists solely as reactive rotamer B or

the rotamers are able to rapidly interconvert at −78 °C. The relative stereochemistry

was established by conversion of cis-255 into known183,184

cis-253 as outlined below

(see Scheme 3.72).

NBoc

HO

O

NBoc

NBoc

SpTol

S

S

pTol

pTol

BH3.SMe2

THF, 67 °C, 1 h

256, 68:32 dr

cis-255, 65%

trans-255, 26%

NBoc

SpTol

1. s-BuLi, TMEDA,

Et2O, _78 °C, 5 min

2. CO2

(R,R)-254

OH

OH

Scheme 3.70

The diastereoselectivity was improved by carrying out a ligand-directed lithiation, an

approach which has previously been used in our group for the synthesis of 2,5-

substituted pyrrolidines.29

Use of s-BuLi/(+)-sparteine surrogate 1 to mediate the

lithiation of (R,R)-254 and trapping with carbon dioxide gave acid 256 in 92:8 dr

(Scheme 3.71). After borane reduction, cis-255 was isolated as the only product in 84%

yield over the two steps; diastereomeric alcohol trans-255 was not isolated after flash

column chromatography.

NBoc

HO

ONBoc

SpTol

SpTolBH3.SMe2

THF, 67 °C, 1 h

256, 92:8 dr cis-255, 88%

NBoc

SpTol

1. s-BuLi, (+)-sp sur 1

Et2O, _78 °C, 5 min

2. CO2

(R,R)-254

OH

Scheme 3.71

Finally, reductive cleavage (Raney-nickel®, THF-EtOH, rt, 5 hours) of the sulfide

moiety gave known183,184

alcohol cis-253 in 73% yield (Scheme 3.72). Comparison of

key diagnostic signals in the 1H NMR spectrum (δH 2.46, dddd, J = 13.5, 11.0, 6.5, 1.0

Hz, 1H, CH) and 13

C NMR spectrum (δC 54.5, CH2OH and 38.8, NCH) to those

provided by Professor Hanessian allowed assignment of the relative configuration of

alcohol cis-253.184

The spectroscopic data for trans-253 was also provided which

confirmed that the other diastereomer was not formed. In addition, the absolute


123

configuration was assigned by comparison of optical rotation: our sample had [α]D +6.6

(c 0.5 in CHCl3) whereas Hanessian’s sample had [α]D +12.0 (c 0.75 in CHCl3).184

NBoc

SpTol

cis-255

OH

Raney-Ni

THF-EtOH, rt, 5 hNBocOH

cis-253, 73%

Scheme 3.72

The synthesis of cis-253 allows assignment of each of the compounds in each of the

synthetic sequence. Importantly, this allows confirmation of the absolute

stereochemistry of the core of sulfoxide syn-(R,R,SS)-225 and, coupled with our

rationale for the sulfoxide configuration (see Scheme 3.50), we can be confident of the

absolute stereochemical assignment. In addition, the stereochemistry of all products

reported in this Chapter formed by sulfoxide → magnesium exchange from sulfoxide

syn-(R,R,SS)-225 can be assigned.


124


The synthesis of a number of α-amino sulfoxides has been attempted. Pyrrolidinyl

sulfoxides anti-(S,SS)-148 and syn-(R,SS)-148 and piperidinyl sulfoxides anti-(S,SS)-149

and syn-(R,SS)-149 could not be formed by either lithiation-trapping or oxidation of α-

amino sulfides (Figure 3.9). We believe that this is due to decomposition of the α-

amino sulfoxides either by cycloreversion or by α-elimination by the nitrogen lone pair.

NBoc

S

O

pTolH

S

O

pTolNBoc

H

ant i-(S,SS)-148

NBoc

S

O

pTolH

syn-(R,SS)-148

S

O

pTolNBoc

H

ant i-(S,SS)-149 syn-(R,SS)-149

Figure 3.9

N-Thiopivaloyl azetidine sulfoxide 192 was synthesised but the yield of the reaction

was disappointing. In addition, acyclic amido sulfoxide 193 and thioamide sulfoxide

194 were successfully isolated. Their synthesis involved a late-stage oxidation by

mCPBA. In addition, acyclic N-Boc dimethylamine sulfoxide 196 was isolated from

the lithiation-trapping of N-Boc dimethyl amine 222. This was the first example of a

stable compound containing the N-Boc α-sulfinyl motif (Figure 3.10).

N

Boc

S

196

O

N

X

Ph

OMe

S

ON

S

S

O

H

192 193, X = O194, X = S

Figure 3.10

We then designed an α-substituted system in which sulfoxide elimination was

prohibited. Indeed, bicyclic sulfoxide syn-(R,R,SS)-225 was synthesised in 99:1 er by

lithiation of N-Boc 4-chloro piperidine 223 using s-BuLi/(R,R)-42 and trapping with

Andersen’s sulfinate (SS)-97 (Figure 3.11). Unfortunately, lithiation of N-Boc 4-chloro

piperidine 223 using s-BuLi/(R,R)-42 and trapping with Andersen’s sulfinate (SS)-97


125

did not lead to the isolation of sulfoxide anti-(S,S,SS)-225 as the major diastereomer in

99:1 er.

NBoc

SpTol

O

syn-(R,R,Ss)-225

Figure 3.11

Subsequently, a sulfoxide → magnesium exchange protocol was successfully developed

for bicyclic sulfoxide syn-(R,R,SS)-225 allowing α-amino Grignard reagent (R,R)-240 to

be formed in 99:1 er. These Grignard reagents were then trapped with an array of

electrophiles to give products as single enantiomers. As an example, ester (S,R)-241

was isolated in 45% yield and 99:1 er over two steps from N-Boc 4-chloro piperidine

223 (Scheme 3.73) In addition, a transmetallation-Negishi coupling protocol was

developed allowing α-arylated products to be isolated in good yields and in 99:1 er.

Sulfoxide syn-(R,R,SS)-225 was also transformed into alcohol cis-253 which constituted

a formal synthesis of saxagliptin.

S

O

NBoc

syn-(R,R,Ss)-225

51%, 99:1 er

NBoc

O

OMeTHF, rt,1 min,

then MeOCOCl

i-PrMgCl

(S,R)-241, 89%

1. s-BuLi, (R,R)-42

Et2O, _78 °C, 1 h

2.

223 SO

O

(SS)-97


NBoc

Cl

Scheme 3.73

Future work should synthesise enantiomeric bicyclic sulfoxide syn-(S,S,RS)-225.

Lithiation of N-Boc 4-chloro piperidine 223 using s-BuLi/(S,S)-42 and trapping with

ent-Andersen’s sulfinate (RS)-97 (Scheme 3.74) would give sulfoxide syn-(S,S,RS)-225

in 99:1 er. Sulfoxide → magnesium of sulfoxide syn-(S,S,RS)-225 would then give

Grignard (S,S)-240 in 99:1 er.


126

1. s-BuLi, (S,S)-42

Et2O, _78 °C, 1 h

2.S

O

223 SO

O

(RS)-97

syn-(S,S,RS)-225 anti-(R,R,RS)-225

NBoc

Cl

NBoc

S

O

NBoc

Reverse Addition

MeN

NMe

tButBu

(S,S)-42

Scheme 3.74

Finally, we still harbour ambitions to synthesise a number of other cyclic α-amino

sulfoxides. However, as the mechanism by which decomposition of α-amino sulfoxides

occurs is still unknown, initial studies should focus on further elucidating this

mechanism.

Chapter Four: Synthesis of N-Thiopivaloyl Azetidine Organolithium Reagents

127

Chapter Four: Synthesis of N-Thiopivaloyl Azetidine

Organolithium Reagents

An expedient method of synthesising α-substituted azetidines is by lithiation-trapping of

N-thiopivaloyl azetidine 101 using chiral organolithium bases (Scheme 4.1). However,

until now, only one example of the asymmetric lithiation-trapping of N-thiopivaloyl

azetidine 101 has been reported and the mechanism of enantiocontrol remained

uncertain.102

N

S

101

N

S

Li

Et2O, _78 °C

s-BuLi, Chiral Diamine E+

N

S

E

257

Scheme 4.1

Our objective was to study the asymmetric lithiation-trapping of N-thiopivaloyl

azetidine 101 using s-BuLi and chiral diamines with a view to establishing the

mechanism by which the enantioselectivity of the products is determined. To do this,

the configurational stability of the lithiated intermediate 257 would need to be

investigated and the electrophilic scope would need to be broadened. Furthermore,

comparisons to N-thiopivaloyl pyrrolidine 210 will be made.


128

4.1 Lithiation-Trapping of N-Thiopivaloyl Azetidines

As well as their appearance in a number of pharmaceutical products,194-196

α-substituted

azetidines are found in a number of natural products. For example, an

antithrombotic,197

mugineic acid,198

peneazetidine A,199

and calydaphinone200

all

contain an α-substituted azetidine and are shown in Figure 4.1.

N

O NH

Br

OMe

NH

O

EtN

NH

C18H39

OH

HO

Penazetidine AMugineic Acid

N

O

MeOOC

HO H

H

Calydapninone

N

HN

HO

COOH

O

OH

OH

COOH

Antithrombotic

Figure 4.1

Azetidines have typically been synthesised by cyclisation of amine nucleophiles onto an

appropriate electrophilic site and these methods have been reviewed in detail by Brandi

et al.101

More recently, lithiation-trapping of N-thiopivaloyl azetidines has provided an

expedient route to α-substituted azetidines.

4.1.1 Racemic Lithiation-Trapping of N-Thiopivaloyl Azetidines

In 2010, Hodgson and Kloesges reported the first lithiation-trapping of N-thiopivaloyl

azetidine 101.102

Interestingly, the rarely-studied N-thiopivalamide group was essential

for high yielding α-lithiation-trapping. Prior to 2010, there is only one reported

example of successfully using the thiopivaloyl group to direct lithiation α to nitrogen.

Seebach and Lubosch carried out the s-BuLi/TMEDA-mediated lithiation of N,N-

dimethyl thiopivalamide 258. Subsequent trapping with a range of electrophiles gave α-

substituted products in 17-82% yield. Selected examples are shown in Scheme

4.2.201,202


129

N

S 2. Electrophile (E+)

1. s-BuLi, TMEDA

THF, _78 °C, 30 min

258

N

S

E

N

S

N

S

4N

S

Ph

OH

N

SOH

Ph

Ph

260, 69%

E+ = n-C5H11I

259, 65%

E+ = MeI

261, 78%

E+ = PhCHO

262, 63%

E+ = Ph2CO

Scheme 4.2

Seebach and co-workers subsequently reported that attempts to use the thiopivalamide

directing group in the lithiation-trapping of 11 other acyclic and cyclic N-

thopivalamides (including that derived from piperidine) were unsuccessful.203

This lack

of versatility may indicate why the thiopivaloyl group has not been more widely

adopted. Furthermore, removal of the thiopivaloyl group can require relatively harsh

conditions. In 1980, Seebach and Lubosch reported three methods for removing the

thioamide functionality.203

In the first method, addition of methyl fluorosulfonate to

aniline derived N-thiopivalamide 263 gave a 3:2 mixture of (E)-264 and (Z)-264 in

quantitative yield. The mixture was then treated with sodium borohydride and basic-

work up gave amine 265 in 58% yield (Scheme 4.3). Unfortunately, using this method

to deprotect products from the lithiation-trapping of N,N-dimethyl thiopivalamide 258

was unsuccessful. This may indicate that aniline moiety is essential for the deprotection

to proceed smoothly.

N

S CH2Cl2, rt, 1.5 h

263

PhMeOSO2F

N

PhMeS

N

MeS

Ph

(Z)-264

(E)-264

1. NaBH4, H2O, DMF,

MeOH, rt, 1h

2. NaOH(aq)

NH

Ph

265, 58%

Scheme 4.3

The second procedure offers a more versatile method for the removal of the thioamide

group, as shown by the deprotection of benzophenone-trapped product 262 (Scheme


130

4.4). Ethylene diamine was added to hydroxy thioamide 262 and heated at reflux. After

cooling to room temperature, hydrochloric acid was added and basic work-up gave

hydroxy amine 266 in 75% yield.

N

S

262

1.H2NCH2CH2NH2

OH

Ph

Ph

NH

266, 75%

OH

Ph

Ph

2. HCl

3. NaOH(aq)

Scheme 4.4

Finally, hydroxy thioamide 262 can also be deprotected using an excess of MeLi to

afford hydroxy amine 266 in 80% yield (Scheme 4.5). These are also the conditions

preferred by Hodgson and Kloesges.102

Presumably, this deprotection proceeds via

nucleophilic attack at the carbonyl of the thioamide group.

N

S

262

1. 5 eq. MeLi, THF,0 °C, 5 h

OH

Ph

Ph

NH

266, 80%

OH

Ph

Ph

2. HCl, H2O

3. NaOH

Scheme 4.5

Despite the limitations of using the N-thiopivalamide protecting group to direct α-

lithiation-trapping, Hodgson and Kloesges found that it gave the best results on the

azetidine system.102

Initial attempts to use more common protecting groups gave

disappointing results (Figure 4.2). For example, lithiation of N-Boc azetidine 267 with

either lithium amides or s-BuLi (both with and without TMEDA) gave no reaction and

N-tert-butylsulfonyl azetidine 268 and N-diethylphosphonyl azetidine 269 similarly

resisted lithiation under a variety of conditions. Furthermore, N-sulfinylazetidine 270

decomposed under lithiation conditions.

NBoc

N N

S

O

OP

OEtO

EtO

267 268 269

N

S

270

O

Figure 4.2

Conversely, lithiation of N-thiopivaloylazetidine 101 using s-BuLi/TMEDA in THF at

−78 °C for 30 minutes and subsequent electrophilic trapping gave α-substituted


131

azetidines rac-102, 271-275 in 83-94% yield (Scheme 4.6). The reaction tolerated a

wide range of electrophiles, including alkyl halides, aldehydes, ketones, trimethylsilyl

chloride and trimethyltin chloride. Interestingly, the product of lithiation and trapping

with benzaldehyde, alcohol syn-rac-273, was reported to be isolated as a single

diastereoisomer.

N

S2. Electrophile (E+)


THF, _78 °C, 30 min

101

N

S

E

N

S

SiMe3N

S

N

S

N

S

OH

Ph

OH

PhPh

H

rac-271, 91%

E+ =Me3SiCl

rac-102, 93%

E+ = MeI

syn-rac-273, 87%

E+ = PhCHO

rac-274, 94%

E+ = Ph2CO

N

S

SnMe3N

S

Bu

rac-272, 86%

E+ =Me3SnCl

rac-275, 83%

E+ = BuBr

Scheme 4.6

More recently, Hodgson and co-workers have reported the lithiation-trapping of N-

thiopivaloyl azetidin-3-ol 276.204

Lithiation of 276 mediated by 3 eq. s-BuLi/6 eq.

TMEDA in THF at −78 °C for 30 minutes and trapping with electrophiles gave 2,3

substituted azetidines rac-277-281 exclusively as the trans-diastereoisomer, with the

exception of the methyl iodide trapped product rac-278 which had a trans:cis ratio of

69:31. Selected results are shown in Scheme 4.7. This reaction proceeds by

deprotonation of the hydroxyl moiety before α-lithiation-trapping.

N

S2. Electrophile (E+)


THF, _78 °C, 30 min

276

N

S

E

N

S

BuN

S

N

S

N

S

rac-277, 68%

E+ = BuI

rac-278, 72%

69:31 dr, E+ = MeI

rac-279, 60%

E+ = Allyl-Br

rac-280, 74%

E+ = BnBr

OH OH

OH OH OH OH

Ph

N

S

SnBu3

rac-281, 82%

E+ = Bu3SnCl

OH

Scheme 4.7


132

In contrast to lithiation-trapping with electrophiles, lithiation-deuteriation occurs

predominantly cis to the hydroxyl group. Lithiation of N-thiopivaloyl azetidin-3-ol 276

using 3 eq. s-BuLi/6 eq. TMEDA and addition of MeOD gave cis-282 as a 90:10

mixture of diastereoisomers (Scheme 4.8). Further mechanistic study showed that the

stereochemical outcome of the lithiation-trapping or lithiation-deuteriation is

independent of which α-proton is removed (cis or trans to the hydroxyl group).

Electrophiles were shown to have a preference for trans-products and protonation

occurs with cis-selectivity.

N

S2. MeOD

1. 3 eq. s-BuLi, 6 eq. TMEDA

THF, _78 °C, 30 min

276

N

S

D

OH OH

cis-282, 90:10 dr100% D

Scheme 4.8

4.1.2 Asymmetric Lithiation-Trapping of N-Thiopivaloyl Azetidines

There is only one example of an asymmetric lithiation-trapping of N-thiopivaloyl

azetidine 101 reported in the literature. Hodgson and Kloesges screened four ligands

and different conditions in order to optimise the asymmetric lithiation and trapping with

methyl iodide to give enantioenriched methylated azetidine (R)-102 or (S)-102.102

The

stereochemical control for each ligand during the lithiation-trapping is summarised in

Scheme 4.9 and Table 4.1. First, the use of (−)-sparteine in Et2O gave (R)-102 in 61:39

er (entry 1) and changing the solvent to hexane gave (R)-102 in 72:28 er (entry 2). Use

of alkoxy amine 283 as the ligand in hexane gave (S)-102 in a disappointing 54:46 er

(entry 3). The use of alkoxy diamine 64 gave (S)-102 in 63:37 er (entry 4) and, finally,

Alexakis diamine129

(R,R)-42 gave (R)-102 in 80:20 er (entry 5).


133

N

S2. MeI

1. 1.2 eq. s-BuLi,1.2 eq. Ligand

Solvent, _78 °C, 30 min

101

N

S

(R)-102

NMe

OLiN

N

OLiMe

N

NH

H

(_)-sparteine 283 64 (R,R)-42

H N

S

(S)-102

H

N

N

tButBu

or

Scheme 4.9

Table 4.1: Asymmetric lithiation-trapping of N-thiopivaloyl azetidine 101

Entry Ligand Solvent er (R:S) Conversion (102:101)a

1 (−)-sparteine Et2O 61:39 99:1

2 (−)-sparteine Hexane 72:28 99:1

3 283 Hexane 46:54 97:3

4 64 Et2O 37:63 78:22

5 (R,R)-42 Et2O 80:20 96b

aConversion determined by GC,

bYield of isolated (R)-102 after column

chromatography

To our surprise, lithiation and trapping proceeded with the opposite sense of induction

to that observed for the asymmetric lithiation-trapping of a number of N-Boc

heterocycles.38,41,136,205

Scheme 4.10 shows a comparison between the lithiation-

trapping of N-Boc pyrrolidine 39 and N-thiopivaloyl azetidine 101 using s-BuLi and

diamine (R,R)-42. Lithiation of N-Boc pyrrolidine 39 using s-BuLi/diamine (R,R)-42 in

Et2O at −78 °C gave intermediate organolithium (S)-40.(R,R)-42. Subsequent trapping

with trimethylsilyl chloride gave (S)-41 in 72% yield and 95:5 er.29

Organolithium (S)-

40 has been previously shown to be configurationally stable at −78 °C and an

enantioselective deprotonation was responsible for the enantioselectivity observed in the

product (see Chapter 1.1.1).38,206


134

N

S

101

N

S

H

NBoc

s-BuLi, (R,R)-42

Et2O, 78 °C, 3 h NBoc

Li.(R,R)-42 NBoc

SiMe3

Me3SiCl

39 (S)-40.(R,R)-4295:5 er

(S)-4172%, 95:5 er

s-BuLi, (R,R)-42

Et2O, 78 °C

30 min

MeI

H H

N

S

Li.(R,R)-42

(R)-10296%, 80:20 er

257.(R,R)-42

Scheme 4.10

In contrast, lithiation of N-thiopivaloyl azetidine 101 using s-BuLi/(R,R)-42 and

trapping with methyl iodide gave (R)-102 in 96% yield and 80:20 er. The

configurational stability of organolithium 257.(R,R)-42 at −78 °C is unknown and,

therefore, the mechanism by which enantiocontrol arises cannot be determined.

Hodgson and Kloesges offered no explanation for the differing enantio-induction

between the systems.


135

4.2 Asymmetric Lithiation-Trapping of N-Thiopivaloyl Azetidine 101

Our objective in this project was to determine the mechanism for the asymmetric

lithiation-trapping of N-thiopivaloyl azetidine 101. An introduction to each of the three

mechanisms (enantioselective deprotonation, dynamic kinetic resolution and dynamic

thermodynamic resolution) was presented in Chapter 1.1.

Due to the opposite sense of induction being observed in the lithiation-trapping of N-

thiopivaloyl azetidine 101 when compared to N-Boc heterocycles with the same ligand,

it seemed unlikely that an enantioselective deprotonation was occurring. However, we

initially considered that there were five possible scenarios that could explain this

difference in selectivity.

1. An enantioselective deprotonation occurs at −78 °C to give an 80:20 mixture of

diastereomeric lithiated intermediates (R)-257.(R,R)-42 and (S)-257.(R,R)-42. The

lithiated intermediates are configurationally stable at −78 °C (Scheme 4.11).

However, the sense of induction of the enantioselective deprotonation was opposite

to that observed N-Boc pyrrolidine 39 due to conformational changes associated

with a reduction in ring size. Alternatively, the sense of induction could be reversed

due to the use of N-thiopivaloyl group rather than N-Boc for directing the lithiation.

N

S

(R)-257.(R,R)-42

Li.(R,R)-42

N

S

(S)-257.(R,R)-42

Li.(R,R)-42

MeIN

S

H

(R)-102

N

S

101

s-BuLi, (R,R)-42 80:

20Et2O, _78 °C

30 min

80:20 er

Scheme 4.11


136

2. An enantioselective deprotonation occurs at −78 °C and proceeds with the same

sense of induction to that observed with N-Boc pyrrolidine 39. This would form an

80:20 mixture of diastereomeric lithiated intermediates, (S)-257.(R,R)-42 and (R)-

257.(R,R)-42, which are configurationally stable at −78 °C. Trapping with methyl

iodide then proceeds with inversion of configuration at −78 °C to give (R)-102 in

80:20 er (Scheme 4.12). This process usually requires stabilised (e.g. benzylic or

allylic) organolithium reagents.23,207

(R)-257.(R,R)-42

(S)-257.(R,R)-42

80:20 er

N

S

Li.(R,R)-42

N

S

Li.(R,R)-42

MeIN

S

H

(R)-102

N

S

101

s-BuLi, (R,R)-42 20:

80Et2O, _78 °C

30 min

Inversion

Scheme 4.12

3. An enantioselective deprotonation occurs at −78 °C to give an unknown mixture of

diastereomeric lithiated intermediates, (S)-257.(R,R)-42 and (R)-257.(R,R)-42,

which are configurationally stable at −78 °C. Methyl iodide does not react with the

organolithium reagents at −78 °C but instead the reaction is allowed to warm up to a

temperature where the lithiated intermediates may interconvert. A dynamic kinetic

resolution then takes place at this elevated temperature whereby, methyl iodide then

reacts preferentially with (R)-257.(R,R)-42 (Scheme 4.13). A similar phenomenon

was responsible for the loss of enantiomeric ratio when lithiated N-Boc piperidine

was trapped with methyl iodide.43


137

(R)-257.(R,R)-42 (S)-257.(R,R)-42

N

S

Li.(R,R)-42

N

S

Li.(R,R)-42

MeIN

S

H

(R)-102

N

S

101

s-BuLi, (R,R)-42

Et2O, _78 °C

30 min

N

S

Li.(R,R)-42

N

S

Li.(R,R)-42

80:20 er_78 °C T

MeIN

S

H

(S)-102

Fast

Slow

(R)-257.(R,R)-42 (S)-257.(R,R)-42

Scheme 4.13

4. The lithiated intermediates are configurationally unstable at −78 °C and, as a result,

the sense of induction does not arise from an enantioselective deprotonation.

Instead, a dynamic kinetic resolution is taking place. Methyl iodide preferentially

reacts with (R)-257.(R,R)-42 to give (R)-102 in 80:20 er (Scheme 4.14).

MeIN

S

H

(R)-102

80:20 er

MeIN

S

H

(S)-102

Fast

Slow

N

S

(R)-257.(R,R)-42

Li.(R,R)-42

N

S

Li.(R,R)-42

N

S

101

s-BuLi, (R,R)-42

Et2O, _78 °C

30 min

(S)-257.(R,R)-42

Scheme 4.14

5. The lithiated intermediates are configurationally unstable at −78 °C and a dynamic

thermodynamic resolution process accounts for the enantiomeric ratio observed in

the product of trapping with methyl iodide. At −78 °C, an 80:20 thermodynamic

ratio of lithiated intermediates (R)-257.(R,R)-42 and (S)-257.(R,R)-42 will form.


138

On addition of methyl iodide, the organolithium reagents are trapped to give (R)-102

in 80:20 er (Scheme 4.15).

(R)-257.(R,R)-42

(S)-257.(R,R)-42

N

S

Li.(R,R)-42

N

S

Li.(R,R)-42

MeIN

S

H

(R)-102

N

S

101

s-BuLi, (R,R)-42

Et2O, _78 °C

30 min

80:20 er

80:

20

Scheme 4.15

Our plan was to design a number of experiments that would reveal which of these

scenarios gives rise to the enantioselectivity. Of utmost importance would be the

determination of the configurational stability of lithiated N-thiopivaloyl azetidine at −78

°C. This would allow us conclude whether the enantioselectivity observed in the

products was due to an enantioselective deprotonation or a dynamic resolution process.

In addition, alternative electrophiles would be used to establish whether the

enantioselectivity was electrophile dependent. Finally, comparisons would be made

between the asymmetric lithiation-trapping of N-thiopivaloyl azetidine 101 and N-

thiopivaloyl pyrrolidine 210. This comparison will expose differences between the four

and five membered heterocycles. Moreover, N-thiopivaloyl pyrrolidine 210 could be

directly compared N-Boc pyrrolidine 39 to observe differences between the N-

thiopivalamide and N-Boc protecting groups.


Azetidine

In order to determine the mechanism by which the asymmetric lithiation-trapping of N-

thiopivaloyl azetidine 101 occurs, it was essential to determine the configurational

stability of the lithiated intermediates. If the organolithium reagent was

configurationally stable at the temperature of the trapping, then we would be able to


139

conclude that an enantioselective deprotonation was occurring. In contrast, if the

organolithium reagent was configurationally unstable at the temperature of trapping

then we could be certain that a dynamic resolution process (kinetic or thermodynamic)

was taking place.18

The method of choice for exploring the configurational stability of the lithiated

intermediate was tin → lithium exchange from an enantioenriched stannane and

trapping with an electrophile. If the enantiomeric ratio of the products after tin →

lithium exchange and trapping was lower than that of the starting stannane, then we can

conclude that the organolithium intermediate was configurationally unstable (see

Scheme 1.22 for an example).

Before conducting the tin → lithium exchange, an asymmetric lithiation-trapping of N-

thiopivaloyl azetidine 101 needed to be carried out in order for us to have a reaction

with which to compare our results. Our choice was using s-BuLi/(−)-sparteine and

trapping with benzaldehyde. The absolute configuration of the products of trapping

lithiated N-thiopivaloyl azetidine with benzaldehyde could be established by

comparison with products synthesised from commerically available (S)-2-azetidine

carboxylic acid. In addition, we were confident that trapping with benzaldehyde would

occur at −78 °C.180

In contrast, with methyl iodide, it has been shown that trapping of

lithiated N-Boc piperidine 48 did not occur until temperatures at which the lithiated

intermediate was configurationally unstable (−40 °C).43

This led to products in reduced

enantiomeric ratio.

N-Thiopivaloylazetidine 101 was lithiated using conditions reported by Hodgson and

Kloesges (1.2 eq. s-BuLi, (−)-sparteine, Et2O, −78 °C, 30 min). Subsequent trapping

with benzaldehyde at −78 °C for 1 hour and quenching the reaction with hydrochloric

acid at −78 °C gave diastereomeric alcohols anti-(S,R)-273 and syn-(R,R)-273 in 9%

yield and 58:42 er and 75% yield and 75:25 er respectively (Scheme 4.16).

Interestingly, Hodgson and co-workers only isolated a single diastereoisomer from the

racemic lithiation-trapping with benzaldehyde.102

We were able to prove the absolute

configuration of alcohols anti-(S,R)-273 and syn-(R,R)-273 by conversion into N-Boc

amino alcohols anti-(S,R)-284 and syn-(R,R)-284 respectively. This was achieved by

removal of the thiopivalamide group using excess MeLi and subsequent Boc protection.


140

In addition, the relative configuration of anti-(S,R)-273 was confirmed by X-ray

crystallography within our group.208

The relative configuration of syn-(R,R)-273 was

confirmed by comparison of the 1H and

13C NMR spectra to those reported in the

literature for syn-rac-273.102

1. 6 eq. MeLi, THF,

0 °C, 5 h2. Boc2O, CH2Cl2,

rt, 16 h

N

S

1. 1.2 eq. s-BuLi, (_)-sparteine

Et2O, _78 °C, 30 min

2. PhCHO, _78 °C, 1 h

3. HCl(aq),_78 °C

N

S

101 anti-(S,R)-273

N

S

syn-(R,R)-273

OH OH

PhPhH H

9%, 58:42 er 75%, 75:25 er

NBoc OH

PhH

NBoc OH

PhH

anti-(S,R)-284

76%, 57:43 er[]D = +14.2

(c 0.6 in CHCl3)

syn-(R,R)-284

71%, 75:25 er

[]D = _1.6

(c 1.1 in CHCl3)

14:86 dr

Scheme 4.16

Enantiomeric N-Boc amino alcohols anti-(R,S)-284 and syn-(S,S)-284 were synthesised

from commerically available (S)-2-azetidine carboxylic acid in order to establish the

absolute configuration (Scheme 4.17). Boc protection of (S)-2-azetidine carboxylic acid

proceeded smoothly to give N-Boc amino acid (S)-285 in 99% yield. Subsequent

EDC/HOBt-mediated amide coupling with N,O-dimethylhydroxylamine.HCl furnished

the Weinreb amide which was reacted directly with PhMgCl to give ketone (S)-286 in a

modest 36% yield over two steps. Reduction of ketone (S)-286 with sodium

borohydride gave diastereomeric alcohols anti-(R,S)-284 (15%) and syn-(S,S)-284

(78%) in 93% overall yield.


141

NH

O

OHH

NBoc

O

OHHBoc2O, NaOH

EtOH/H2O, rt, 16 h NBoc

O

NHMe

OMeMe

H.HClN

OMe , NMM

HOBt, EDC, DMF, rt, 18 h

NBoc

O

PhH

PhMgCl

THF,_78 °C, 2 h

NBoc

OH

PhH

NBoc

OH

PhHNaBH4

MeOH, rt, 30 min

(S)-285, 99%

anti-(R,S)-284

15%, 99:1 er

[]D = _88.5

(c 1.05 in CHCl3)

syn-(S,S)-284

78%, 99:1 er

[]D = +1.1(c 1.3 in CHCl3)

(S)-286, 36%85:15 dr

Scheme 4.17

By comparison of optical rotation and CSP-HPLC data between alcohols anti-284 and

syn-284 synthesised from lithiation-trapping and those obtained from (S)-2-azetidine

carboxylic acid, we concluded that lithiation-trapping proceeded with the opposite sense

of induction to that reported by Hodgson and Kloesges.102

Indeed, lithiation of N-

thiopivaloyl azetidine 101 using s-BuLi/(−)-sparteine and trapping with methyl iodide

gave (R)-102 in 61:39 er (Scheme 4.18). In contrast, when we trapped the reaction with

benzaldehyde, diastereomeric alcohols anti-(S,R)-273 and syn-(R,R)-273 were isolated

in 58:42 er and 75:25 er respectively. This difference clearly indicated that the

enantioselectivity of the lithiation-trapping procedure is electrophile dependent.

N

S

101

N

S

H

(R)-102, 61:39 er


Et2O, _78 °C, 30 min

2. MeIHodgson:

N

S


Et2O, _78 °C, 30 min

2. PhCHON

S

101 ant i-(S,R)-273

N

S

syn-(R,R)-273

OH OH

PhPhH H

9%, 58:42 er 75%, 75:25 er

14:86 dr

Our Result:

Scheme 4.18

With a suitable comparison reaction in hand, attention turned to the configurational

stability study using tin → lithium exchange. The required stannane was synthesised by


142

asymmetric lithiation of N-thiopivaloyl azetidine 101 using s-BuLi/(−)-sparteine and

trapping with trimethyltin chloride. Stannane (S)-272 was isolated in 55% yield and

68:32 er (Scheme 4.19). The stereochemical assignment was not proven but was

assigned by analogy with the enantioinduction observed in the benzaldehyde trapping.

N

S


Et2O, _78 °C, 30 min

2. Me3SnClN

S

101 (S)-272

SnMe3

55%, 68:32 er Scheme 4.19

With stannane (S)-272 in hand, the configurational stability of the intermediate

organolithium reagent at −78 °C was investigated. Treatment of (S)-272 with n-BuLi in

THF at −78 °C for 5 minutes and trapping with benzaldehyde gave diastereomeric

alcohols anti-rac-273 and syn-rac-273 in 26% yield and 58% yield respectively

(Scheme 4.20). Both alcohols were isolated in 50:50 er. Thus, we conclude that under

these reaction conditions (THF, −78 °C) lithiated intermediate 257.THF was

configurationally unstable over 5 minutes.

N

S

(S)-272, 68:32 er

SnMe3N

S

Li

THF, _78 °C

5 min

n-BuLi

O

O

1. PhCHON

S

syn-rac-273

OH

PhH

58%, 50:50 er

N

S

anti-rac-273

OH

PhH

26%, 50:50 er257.THF

2. HCl(aq)

25:75 dr

Scheme 4.20

The conditions used for the tin → lithium exchange reaction (THF, −78 °C) are

significantly different to those used for the asymmetric lithiation of N-thiopivaloyl

azetidine 101 (diamine, Et2O, −78 °C). It is possible that the introduction of a diamine

to the tin → lithium exchange protocol may result in a configurationally stabilised

lithiated intermediate and thus, after trapping with benzaldehyde, enantioenriched

products may be isolated. Therefore, tin → lithium exchange mediated by n-

BuLi/TMEDA in Et2O at −78 °C for 5 minutes and trapping with benzaldehyde was


143

undertaken. However, this also led to the isolation of diastereomeric alcohols anti-rac-

273 (24%) and syn-rac-273 (61%) in 50:50 er (Scheme 4.21).

N

S

(S)-272, 68:32 er

SnMe3N

S

Li

Et2O, _78 °C, 5 min

n-BuLi, TMEDAN

N

1. PhCHO N

S

syn-rac-273

OH

PhH

61%, 50:50 er

N

S

anti-rac-273

OH

PhH

24%, 50:50 er257.TMEDA

2. HCl(aq)

24:76 dr

Scheme 4.21

From the tin → lithium exchange reactions, it was concluded that lithiated N-

thiopivaloyl azetidine was configurationally unstable at −78 °C. This was unexpected

because lithiated N-Boc pyrrolidine and piperidine are configurationally stable under

these conditions.52,56

Further discussion of this difference is presented in Chapter 4.3.

Use of a substoichiometric amount of electrophile can be used to detect whether a

lithiated intermediate is configurationally stable on the timescale of reaction with the

electrophile. This approach was christened “the poor man’s Hoffmann test” by Beak et

al. in 1996.209

If a change in enantioselectivity is observed with a substoichiometric

amount of electrophile when compared to an excess of electrophile, then it can be

concluded that the organolithium is configurationally stable on the timescale of reaction

with the electrophile. If the same enantiomeric ratio is observed in both reactions then

no definitive conclusion can be drawn.210

An example of the “poor man’s Hoffmann test” is shown in Scheme 4.22.210

Benzylic

organolithium reagents (R)-288 and (S)-288 were trapped with an excess of

trimethylsilyl chloride to give silylated products (R)-289 in 88:12 er. When the reaction

was repeated with just 0.17 eq. of trimethylsilyl chloride, (R)-289 was isolated in 80:20

er. This change in enantiomeric ratio led to the conclusion that the lithiation

intermediate showed a degree of configurational stability on the timescale of reaction

with the electrophile.


144

Ph NH

O

Ph NH

OMe3Si HPh NLi

OH

>1 eq. Me3SiCl: 88:12 er0.17 eq. Me3SiCl: 80:20 er

(R)-289

Me3SiCl

(_)-sp.Li

Ph NLi

OH(_)-sp.LiTHF, _78 °C

(R)-288

(S)-288

287

+

2 eq. s-BuLi

(_)-sparteine

Scheme 4.22

Hence, we carried out the lithiation of N-thiopivaloyl azetidine 101 using s-BuLi/(−)-

sparteine and trapped with 0.3 equivalents of benzaldehyde (Scheme 4.23). From this

reaction, diastereomeric alcohols anti-(S,R)-273 and syn-(R,R)-273 were isolated in 3%

yield and 58:42 er and 23% yield and 82:18 er respectively. Yields are with respect to

N-thiopivaloyl azetidine 101.

N

S


Et2O, _78 °C, 30 min

2. 0.3 eq. PhCHO_78 °C, 1 h

3. 1M HCl(aq),_78 °C

N

S

101 ant i-(S,R)-273

N

S

syn-(R,R)-273

OH OH

PhPhH H

3%, 58:42 er 23%, 82:18 er

Scheme 4.23

The enantiomeric ratio of the minor diastereomer, anti-(S,R)-273, isolated from the

reaction with substoichiometric electrophile was the same as that isolated from the

reaction with excess electrophile (see Scheme 4.16). Furthermore, only a small

difference in enantiomeric ratio was observed in alcohol syn-(R,R)-273 (82:18 er vs.

75:25 er). Therefore, we cannot draw any definitive conclusions on the configurational

stability of the organolithium reagents with respect to rate of trapping with the

electrophile.

It is thus concluded that the lithiated azetidine is configurationally unstable at −78 °C.

Therefore, we were confident that the enantioselectivity of the asymmetric lithiation-

trapping of N-thiopivaloyl azetidine 101 was not determined by an enantioselective

deprotonation mechanism. Instead, a dynamic resolution process is taking place but, at

this point, we cannot be certain whether this process is kinetic or thermodynamic in

nature.


145

4.2.2 Dynamic Resolution of Lithiated N-Thiopivaloyl Azetidine

The conclusion from the configurational stability study was that a dynamic resolution

process was occurring. To prove this, it should be possible to resolve a racemic

lithiated intermediate by the addition of a chiral diamine. The chiral diamine ligand

would then cause either one diastereomeric lithiated intermediate to react faster on

addition of an electrophile (dynamic kinetic resolution, see Chapter 1.1.2) or a

thermodynamic ratio of diastereomeric lithiated intermediates would form which would

then be trapped with an electrophile (dynamic thermodynamic resolution, see Chapter

1.1.3).

Therefore, n-BuLi/(−)-sparteine was added to stannane rac-272 (Et2O, −78 °C, 5

minutes) and trapped with benzaldehyde. This gave diastereomeric alcohols anti-(R,S)-

273 and syn-(R,R)-273 in 62:38 er and 73:27 er respectively (Scheme 4.24). The

enantiomeric ratios of the products are similar to those obtained by asymmetric

lithiation of N-thiopivaloyl azetidine 101: alcohol anti-(R,S)-273 was isolated in 58:42

er and alcohol syn-(R,R)-273 was isolated in 75:25 er (see Scheme 4.16). This result

proves that a dynamic resolution process is indeed occurring.

N

S


Et2O, _78 °C, 5 min

rac-272

N

S

OH

PhH

N

S

OH

PhH

SnMe3

2. PhCHO, _78 °C, 1 h

3. HCl(aq),_78 °C

anti-(R,S)-27310%, 62:38 er

syn-(R,R)-27388%, 73:27 er

Scheme 4.24

In order to better recreate the direct lithiation conditions, formation of a racemic

lithiated intermediate starting from N-thiopivaloyl azetidine 101 was attempted. Since

it is known that (−)-sparteine is unable to displace TMEDA and THF from the lithiated

intermediate,127

Hodgson and Kloesges’ original conditions for the racemic lithiation of

N-thiopivaloyl azetidine 101 (s-BuLi/TMEDA, THF, −78 °C 30 minutes) were not

suitable. Hence, we attempted to find a protocol for the racemic lithiation of N-

thiopivaloyl azetidine 101 in the absence of TMEDA and THF.


146

To our delight, lithiation of N-thiopivaloyl azetidine 101 mediated by s-BuLi in Et2O at

−40 °C for 1 hour and trapping with benzaldehyde gave diastereomeric alcohols anti-

rac-273 and syn-rac-273 in 21% yield and 41% yield respectively (Scheme 4.25). It is

possible that the reduction in yield may be due to the competitive addition of s-BuLi or

the lithiated intermediate to the thiopivaloyl group. However, thiols of type 290 were

not isolated from the reaction.

N

S

1. s-BuLi,

Et2O, _40 °C, 1 h

2. PhCHO

101

N

S

syn-rac-273

OH

PhH

42%

N

S

anti-rac-273

OH

PhH

21%

SH

R

R

290not isolated

Scheme 4.25

With a procedure for the formation of the racemic lithiated intermediate in hand, a

dynamic resolution process was attempted. N-Thiopivaloyl azetidine 101 was lithiated

by s-BuLi in Et2O at −40 °C to give the racemic lithiated intermediate. The reaction

was then cooled to −78 °C and (−)-sparteine was added. However, after trapping with

benzaldehyde, alcohols anti-rac-273 (19%) and syn-rac-273 (43%) were isolated in

50:50 er (Scheme 4.26).

N

S

Li

OEt2

OEt2

(_)-sparteineN

S

1. s-BuLi, Et2O_40 °C, 1 h

2. _78 °C

15 min

101

N

S

syn-rac-273

OH

PhH

43%, 50:50 er

N

S

ant i-rac-273

OH

PhH

19%, 50:50 er

N

S

Li.(_)-spN

S

Li.(_)-sp

_78 °C, 1 h257.Et2O

257.Et2O

PhCHO

1. PhCHO, _78 °C, 1 h

2. 1M HCl(aq)

Scheme 4.26


147

This result is at odds with the tin → lithium exchange approach presented in Scheme

4.24. Our hypothesis was that (−)-sparteine was not complexing to the lithium at −78 °C

and hence racemic lithiated intermediate 257.Et2O was being trapped by benzaldehyde

giving racemic products. It was postulated that we could perturb the binding kinetics

by carrying out the complexation with (−)-sparteine at higher temperature. Therefore,

the reaction was repeated but adding (−)-sparteine at −40 °C and incubating at this

temperature for 15 minutes (Scheme 4.27). The reaction was then cooled to −78 °C for

1 hour before benzaldehyde was added. This gave alcohol anti-(S,R)-273 in 7% yield

and 59:41 er and alcohol syn-(R,R)-273 in 58% yield and 72:28 er respectively.

Crucially, isolation of products with similar levels of enantioenrichment to those from

direct lithiation-trapping at −78 °C (see Scheme 4.16) allows us to conclude that a

dynamic resolution process is occurring under the reaction conditions.

1. PhCHO, _78 °C, 1 h

2. 1M HCl(aq),_78 °C

257.Et2ON

S

Et2O_40 °C, 1 h

101

N

S

syn-(R,R)-273

OH

PhH

57%, 71:29 er

N

S

ant i-(S,R)-273

OH

PhH

7%, 59:41 er

N

S

Li.(_)-spN

S

Li.(_)-sp1. (_)-sparteine,

_40 °C, 15 min

2. _78 °C, 1 h

s-BuLi

N

S

Li

OEt2

OEt2

257.Et2O

Scheme 4.27

Temperature can have a dramatic effect on the dynamic resolution processes.53,54,56

In a

dynamic kinetic resolution, a change in temperature can affect the rates at which each of

the diastereomeric lithiated intermediates reacts with the electrophile. This change of

rate is reflected in the enantiomeric ratio of the products. In addition, in a dynamic

thermodynamic resolution, a change in temperature can affect the diastereomeric ratio

of the lithiated intermediates. When an electrophile is added, this diastereomeric ratio

determines the enantiomeric ratio of the products. Therefore, we wanted to investigate

the effect of changing the temperature in the lithiation-trapping of N-thiopivaloyl

azetidine 101.


148

N-Thiopivaloyl azetidine 101 was lithiated using s-BuLi/(−)-sparteine (Et2O, −78 °C, 30

minutes). The reaction was then warmed to a higher temperature and incubated at that

temperature for 1 hour. Subsequent trapping with benzaldehyde gave diastereomeric

alcohols anti-(S,R)-273 and syn-(R,R)-273 (Scheme 4.28, Table 4.2). For comparison,

the lithiation-trapping of N-thiopivaloyl azetidine 101 at −78 °C is reported in entry 1.

When the reaction was warmed to −50 °C, trapping with benzaldehyde led to the

isolation of alcohol anti-(S,R)-273 in 13% yield and 58:42 er and alcohol syn-(R,R)-273

in 82% yield and a slightly reduced 68:32 er (entry 2) when compared to the

enantiomeric ratio at −78 °C.

N

S


Et2O, _78 °C, 30 min

2. T °C, 1 h3. PhCHO

N

S

101 anti-(S,R)-273

N

S

syn-(R,R)-273

OH OH

PhPhH H

Scheme 4.28

Table 4.2: Temperature effect on the enantioselectivity of the lithiation-trapping of N-

thiopivaloyl azetidine 101

Entry T (°C) anti-(S,R)-273 syn-(R,R)-273

Yield (%) er (S,R):(R,S) Yield (%) er (R,R):(S,S)a

1 −78b 9 58:42 75 75:25

2 −50 13 58:42 82 68:32

3 −40 14 56:44 84 62:38

4 −30 11 55:45 76 59:41

5 −30c 7 59:41 72 75:25


bLithiation and trapping conducted at this temperature,

cReaction cooled to −78 °C for 30 min before addition of electrophile.

More significant reductions in enantioselectivity were observed in the major

diastereoisomer when warming to −40 °C and −30 °C. Indeed, alcohol anti-(S,R)-273

was isolated in 14% yield and 56:44 er and alcohol syn-(R,R)-273 in 84% yield and

62:38 er at −40 °C (entry 3). Alcohol anti-(S,R)-273 was isolated in 11% yield and

55:45 er and alcohol syn-(R,R)-273 in 76% yield and only 59:41 er at −30 °C (entry 4).

Finally, we carried out a lithiation-trapping with a warm cool cycle. N-Thiopivaloyl


149

azetidine 101 was lithiated using s-BuLi/(−)-sparteine at −78 °C for 30 minutes. Then,

the reaction was warmed to −30 °C and stirred at this temperature for 1 hour, before

cooling to −78 °C and incubating for a further 30 minutes. Subsequent electrophilic

trapping with benzaldehyde gave diastereomeric alcohols anti-(S,R)-273 and syn-(R,R)-

273 in 7% and 59:41 er and 72% and 75:25 er respectively (entry 5). Significantly, the

products isolated had equivalent enantioselectivity to those isolated from the direct

lithiation-trapping at −78 °C. This further proves that the lithiated intermediate is

configurationally unstable at −78 °C.

The lithiation of N-thiopivaloyl azetidine 101 using s-BuLi/(−)-sparteine in Et2O at

−100 °C was also attempted (Scheme 4.29). Trapping with benzaldehyde gave alcohol

anti-(S,R)-273 in 7% yield and 57:43 er and alcohol syn-(R,R)-273 in 66% yield and

77:23 er. It is unknown if lithiated N-thiopivaloyl azetidine 101 is configurationally

unstable at this temperature.

101 anti-(S,R)-273 syn-(R,R)-273


Et2O, _100C, 30 min

2. PhCHO

N

S

N

S

Ph

OH

H

N

S

Ph

OH

H

7%, 57:43 er 66%, 77:23 er

Scheme 4.29

Using different chiral ligands can have a dramatic effect on the enantioselectivity of the

dynamic resolution process.52,56

Therefore, the lithiation-trapping of N-thiopivaloyl

azetidine 101 was carried out using other diamine ligands (Scheme 4.30, Table 4.3).

For comparison, the result when (−)-sparteine was used as the ligand is presented in

entry 1. Diamine 42 had previously given the highest enantiomeric ratio in the

lithiation-trapping of N-thiopivaloyl azetidine 101 reported by Hodgson.102

In our

hands, lithiation of N-thiopivaloyl azetidine 101 using s-BuLi/(S,S)-42 and trapping

with benzaldehyde gave alcohol anti-(R,S)-273 in 20% yield and 65:35 er and alcohol

syn-(S,S)-273 in 73% yield and 53:47 er (entry 2). Disappointingly, this was not an

improvement on the use of (−)-sparteine as the ligand.


150

N

S

1. s-BuLi, Ligand

Et2O, _78 °C, 30 min

2. PhCHON

S

101 ant i-(R,S)-273

N

N

tButBu

(S,S)-42

N

S

syn-(S,S)-273

OH OH

PhPhH H

N

N


N

NH

H

(_)-Sparteine

H

Scheme 4.30

Table 4.3: Asymmetric lithiation-trapping of N-thiopivaloyl azetidine 101 using s-

BuLi/chiral ligands.

Entry Ligand anti-(R,S)-273 syn-(S,S)-273

Yield (%) er (R,S):(S,R)a Yield (%) er (S,S):(R,R)

a

1 (−)-sparteine 9 42:58 75 25:75

2 (S,S)-42 20 65:35 73 53:47

3 (+)-sp. surr. 1 7 54:46 70 54:46


Lithiation of N-thiopivaloyl azetidine 101 using s-BuLi/(+)-sparteine surrogate 1 and

trapping with benzaldehyde gave alcohol anti-(R,S)-273 in 7% yield and alcohol syn-

(S,S)-273 in 70% yield, with both diastereoisomers giving a disappointing 54:46 er

(entry 3). This was surprising given that (+)-sparteine surrogate 1 typically gives

enantiomeric ratios of similar magnitude to (−)-sparteine.19

In this case, the

enantiomeric ratios are much lower when (+)-sparteine surrogate 1 is used as the ligand.

This disparity has been previously observed in dynamic kinetic and dynamic

thermodynamic resolutions and this lends further support to an enantioselective

deprotonation not taking place under the asymmetric lithiation conditions.20

The s-BuLi/(+)-sparteine surrogate 1 complex has been shown to be more reactive

towards lithiation than s-BuLi/(−)-sparteine.43

Therefore, it was postulated that

deprotonation of N-thiopivaloyl azetidine 101 may occur in the presence of

benzaldehyde giving the intermediate organolithium reagent which would immediately

react with benzaldehyde. This experiment would give an indication if an initial


151

enantioselective deprotonation occurred prior to equilibration of the diastereomeric

lithiated intermediates.

Hence, s-BuLi/(+)-sparteine surrogate 1 was added to N-thiopivaloyl azetidine 101 and

benzaldehyde (Scheme 4.31). After purification by flash column chromatography,

alcohol anti-(R,S)-273 was isolated in 0.5% yield and 56:44 er and alcohol syn-(S,S)-

273 was isolated in 1.5% yield and 60:40 er.

N

S

s-BuLi, PhCHO(+)-sp. surrogate 1

N

S

101 anti-(R,S)-273

N

S

syn-(S,S)-273

OH OH

PhPhH H

0.5%, 56:44 er

N

N

(+)-sparteinesurrogate 11.5%, 60:40 er

Et2O, _78 °C, 30 min

H

Scheme 4.31

The enantiomeric ratio of anti-(R,S)-273 is the same as that from the lithiation of N-

thiopivaloyl azetidine 101 and subsequent trapping with benzaldehyde. In contrast,

there is a slight improvement in the enantiomeric ratio of syn-(S,S)-273. It is possible

that this indicates the initial deprotonation has a higher enantioselectivity than that

observed in the trapped products.

In summary, we have shown that a dynamic resolution process is occurring at −78 °C

during the lithiation-trapping of N-thiopivaloyl azetidine 101. A racemic lithiated

intermediate, formed either by tin → lithium exchange or racemic lithiation of N-

thiopivaloyl azetidine 101, was successfully resolved. Currently, we have not been able

to prove whether a dynamic kinetic resolution or a dynamic thermodynamic resolution

is taking place with benzaldehyde.

4.2.3 Lithiation of N-Thiopivaloyl Azetidine 101 and Trapping with Methyl Iodide

Our attention turned to using methyl iodide as the electrophile in the lithiation-trapping

of N-thiopivaloyl azetidine 101. Of particular interest was investigating the reason for

the opposite sense of induction when using methyl iodide when compared to what we

have shown for benzaldehyde (see Scheme 4.18).102

We had three hypotheses that

could explain this difference. These are summarised in Schemes 4.32, 4.33 and 4.34 for

the lithiation using (−)-sparteine as the ligand. In the first mechanism, a dynamic


152

kinetic resolution was occurring when trapping with either methyl iodide or

benzaldehyde. However, methyl iodide would react preferentially with organolithium

(R)-257.(−)-sp, whereas benzaldehyde reacts faster with the organolithium reagent (S)-

257.(−)-sp (Scheme 4.32). The difference in rates of trapping would arise from the

different energies of the transition states.

N

S

(R)-257.(_)-sp

Li.(_)-sp

N

S

(S)-257.(_)-sp

Li.(_)-sp

MeIN

S

H

(R)-102

PhCHO

anti-(S,R)-273 syn-(R,R)-273

N

S

Ph

OH

H

N

S

Ph

OH

H

Scheme 4.32

Alternatively, both electrophiles react preferentially with organolithium (S)-257.(−)-sp

but methyl iodide reacts with inversion of configuration at carbon to give (R)-102

(Scheme 4.33). The reaction of organolithium reagents with methyl iodide proceeding

with inversion of configuration has been previously observed although typically a

stabilised (e.g. allylic or benzylic) organolithium reagent is necessary.207

N

S

(R)-257.(_)-sp

Li.(_)-sp

N

S

(S)-257.(_)-sp

Li.(_)-sp

or MeIN

S

H

(R)-102

PhCHO

ant i-(S,R)-273 syn-(R,R)-273

N

S

Ph

OH

H

N

S

Ph

OH

H

or

Product of Inversion

Scheme 4.33


153

In the third scenario, we propose that a dynamic thermodynamic resolution is occurring

with the fast trapping benzaldehyde electrophile. Therefore, the outcome is dependent

upon the diastereomeric ratio of the organolithium intermediates. Based on the

enantiomeric ratios of anti-(S,R)-273 and syn-(R,R)-273 we suggest that the

diastereomeric ratio of (S)-257.(−)-sp and (R)-257.(−)-sp would be ca. 70:30 dr at −78

°C. In contrast, when methyl iodide is used as the electrophile, a dynamic kinetic

resolution process takes place. This could be due to the slower reacting nature of

methyl iodide when compared to benzaldehyde (Scheme 4.34).

N

S

(R)-257.(_)-sp

Li.(_)-sp

N

S

(S)-257.(_)-sp

Li.(_)-sp

PhCHO

ant i-(S,R)-273 syn-(R,R)-273

N

S

Ph

OH

H

N

S

Ph

OH

H

N

S

(R)-257.(_)-sp

Li.(_)-sp

N

S

(S)-257.(_)-sp

Li.(_)-sp

MeIN

S

H

(R)-102

Scheme 4.34

Our plan was to design a number of experiments that would distinguish between these

mechanisms. In the first place, we wanted to investigate whether the lithiated

intermediate was trapped by methyl iodide at −78 °C. Therefore, the lithiation of N-

thiopivaloyl azetidine 101 using s-BuLi/(−)-sparteine was carried out and methyl iodide

was added at −78 °C (Scheme 4.35). The reaction was then incubated at −78 °C for 2

hours before benzaldehyde was then added. If methyl iodide reacts at −78 °C then we

would expect the formation of (S)-102 as the only product. However, if the lithiated

intermediate is not trapped by methyl iodide at −78 °C then alcohols anti-(S,R)-273 and

syn-(R,R)-273 would be isolated. This reaction gave methyl azetidine (S)-102 in 78%

yield and 58:42 er. The products of trapping with benzaldehyde, alcohols anti-(S,R)-

273 and syn-(R,R)-273, were not evident in the 1H NMR spectrum of the crude product

indicating that all the lithiated intermediate had reacted with the methyl iodide prior to

the addition of benzaldehyde.


154

N

S

ant i-(S,R)-273

N

S


Et2O, _78 °C, 30 min

2. MeI, _78 °C, 2 h

3. PhCHO, _78 °C, 1 h

N

S

101 (S)-10278%, 58:42 er

N

S

syn-(R,R)-273

OH OH

PhPhH H

Not Formed Not Formed

H

Scheme 4.35

Most significantly, what we believe to be the opposite enantiomer to that reported in the

literature was isolated from this reaction (see stereochemical assignment in Scheme

4.37). Furthermore, repeating this reaction under the same conditions reported by

Hodgson and Kloesges gave methyl azetidine (S)-102 in 91% yield and 59:41 er

(Scheme 4.36). This is the same major enantiomer as we observed when trapping with

benzaldehyde. In contrast, Hodgson and Kloesges reported that this reaction gave

methyl azetidine (R)-102 in 61:39 er (see Scheme 4.9 and Table 1.1).102

N

S


Et2O, _78 °C, 30 min

2. MeIN

S

101 (S)-10291%, 59:41 er

H

Scheme 4.36

The best enantiomeric ratio reported for trapping the lithiated intermediate with methyl

iodide was achieved with diamine (R,R)-42. Indeed, methyl azetidine (R)-102 was

isolated in 96% yield and 80:20 er (see Scheme 4.9 and Table 1.1). We conducted the

enantiomeric reaction, namely the lithiation of N-thiopivaloyl azetidine 101 using s-

BuLi/diamine (S,S)-42 and trapping with methyl iodide. To our surprise, methyl

azetidine (R)-102 was isolated in 87% yield and 69:31 er (Scheme 4.37). This is the

same enantiomer to that reported by Hodgson and therefore opposite to what we were

expecting to isolate. Comparison of optical rotation for (R)-102 to that reported in the

literature allowed assignment of absolute configuration.


155

N

S

1. s-BuLi, (S,S)-42

Et2O, _78 °C, 30 min

2. MeI, _78 °C, 1 h

3. 1M HCl(aq)

N

S

101 (R)-10287%, 69:31 er

[]D = _2.0 (c 0.95 in CHCl3)

lit.102 []D = _21.3

(c 1.15 in CHCl3 for 99:1 er)

H

N

N

tButBu

(S,S)-42

Scheme 4.37

Attempts were made to improve the enantioselectivity of the lithiation-trapping

procedure by adding methyl iodide over 2 hours. A similar effect has been reported by

Coldham et al. in the dynamic kinetic resolution of N-Boc-2-lithiopyrrolidine (Scheme

4.38).54

Indeed, tin → lithium exchange of stannane rac-291 using n-BuLi/58 in Et2O

at −78 °C and then warming to −20 °C before slow addition of trimethylsilyl chloride

over 90 minutes gave silylated pyrrolidine (S)-41 in 96:4 er. Warming to −20 °C was

necessary to ensure that enantiomerisation of the lithiated intermediate could occur.

The 96:4 er achieved by this slow addition approach is in contrast to the isolation of

(R)-41 in 58:42 er when trimethylsilyl chloride was added in one portion.

NBoc

SnBu3 NBoc

SiMe3

H

1. n-BuLi, 58

Et2O, _78 °C

2. Me3SiCl, _20 °C

(S)-4154% 96:4 er

291

orNBoc

SiMe3

H

(R)-4165% 58:42 er

Me3SiCl added

over 90 min

Me3SiCl added

in one portion

NOLi

MeN

58

Scheme 4.38

N-Thiopivaloyl azetidine 101 was lithiated using s-BuLi/(S,S)-42 and then methyl

iodide was added over 2 hours at −78 °C (Scheme 4.39). This gave methyl azetidine

(R)-102 in 91% yield and 68:32 er. Unfortunately, no improvement in enantiomeric

ratio was observed when compared to adding the electrophile in one portion (69:31 er,

see Scheme 4.37).


156

N

S

1. s-BuLi, (S,S)-42

Et2O, _78 °C, 30 min

2. MeI added over 2 hN

S

101 (R)-10291%, 68:32 er

H

N

N

tButBu

(S,S)-42

Scheme 4.39

Due to the rather small optical rotation value for our synthesised sample of (R)-102, we

attempted to transform it into known N-Boc methyl azetidine (R)-292 which has a

higher optical rotation value ([α]D −40.5 (c 0.80 in CHCl3)).102

This would confirm that

our stereochemical assignment was correct. Unfortunately, removal of the thiopivaloyl

group using MeLi and subsequent protection using Boc2O was unsuccessful (Scheme

4.40).

1. MeLi, THF, 0 °C, 5 h

2. Boc2O, CH2Cl2, rt, 16 h NBoc

(R)-292

N

S

(R)-102, 69:31 er

HH

Scheme 4.40

We then set about the synthesis of (R)-292 starting from N-Boc acid (S)-285 (previously

prepared from commerically available (S)-2-azetidine carboxylic acid, see Scheme

4.14). First, acid (S)-285 was reduced to alcohol (S)-293 in 93% yield using BH3.SMe2

(Scheme 4.41). Treatment of alcohol (S)-293 under Appel iodination conditions

(iodine, triphenylphosphine, imidazole) gave iodide (S)-294 in 85% yield. Finally,

hydrogenolysis of (S)-294 gave N-Boc methyl azetidine (R)-292 in 75% yield.

NBoc

O

OHH

THF, 67 °C, 2 h

NBoc

H

(R)-292, 75%

NBoc

OHH

NBoc

IHBH3.SMe2

CH2Cl2, rt, 16 h

I2, PPh3, Im.

MeOH, rt, 16 h

Pd/C, H2, Et3N

(S)-285 (S)-293, 93% (S)-294, 85%

[]D = _38.1 (c 1.0 in CHCl3)

lit.102 []D = _40.4 (c 0.8 in CHCl3)

Scheme 4.41


157

The conversion of N-Boc methyl azetidine (R)-292 into N-thiopivaloyl methyl azetidine

(R)-102 has been previously reported.102

Therefore, we repeated this reaction under the

same conditions (Scheme 4.42). Unfortunately, (R)-102 was not evident in the 1H NMR

spectrum of the crude product. No improvements were obtained when repeating the

reaction and any attempts to isolate the N-pivalamide intermediate were unsuccessful.

In addition, alternative acylation conditions (Et3N, DMAP, CH2Cl2) did not lead to any

of the desired product being isolated.

H

NBoc

H

N

S3. P2S5, 75 °C, 6 h

1. TFA, CH2Cl2, rt, 1 h

2. PivCl, py., rt, 16 h

(R)-102(R)-292 Scheme 4.42

Whilst the absolute configuration of methyl azetidine (R)-102 has not been

unequivocally established, we are confident that, despite the small magnitude of the

optical rotation, the sense of induction for the lithiation of N-thiopivaloyl azetidine 101

and trapping with methyl iodide is the same as that observed when trapping with

benzaldehyde. This conclusion is in contradiction to the sense of induction reported by

Hodgson and Kloesges and therefore further proof will need to be garnered prior to

publication.

So far, we have shown that lithiated N-thiopivaloyl azetidine 101 is configurationally

unstable at −78 °C. Thus, an enantioselective deprotonation mechanism cannot be

invoked to explain the enantioselectivity observed in the products from lithiation-

trapping reactions. Instead, a dynamic resolution process must be occurring. We are

currently unable to determine whether a dynamic kinetic or a dynamic thermodynamic

resolution is occurring under the asymmetric lithiation conditions. Interestingly, the

products isolated from the lithiation-trapping of N-thiopivaloyl azetidine 101 have the

opposite configuration to that reported by Hodgson and Kloesges.102

The configurational instability of lithiated N-thiopivaloyl azetidine at −78 °C is

remarkable when compared to lithiated N-Boc pyrrolidine and piperidine, both of which

are configurationally stable at −78 °C. We suggest that the configurational instability

of lithiated N-thiopivaloyl azetidine is due to either the smaller ring size or the N-


158

thiopivaloyl protecting group. Therefore, our next goal was to investigate the

asymmetric lithiation of N-thiopivaloyl pyrrolidine 210.


159

4.3 Lithiation-Trapping of N-Thiopivaloyl Pyrrolidine 210

In light of lithiated N-thiopivaloyl azetidine 101 being configurationally unstable at −78

°C, we were interested in investigating the configurational stability of lithiated N-

thiopivaloyl pyrrolidine 210. This comparison would allow us to determine whether the

configurational instability of the lithiated intermediate at −78 °C was due to the

reduction in ring size or the thiopivaloyl protecting group.

It has previously been shown that lithiated N-Boc pyrrolidine 210 is configurationally

stable at −78 °C.54,76

For example, Beak and Gross reported that the tin → lithium

exchange of stannane (S)-295 (95:5 er) using n-BuLi in THF at −78 °C for 2 hours and

trapping with dimethyl sulfate gave methylated pyrrolidine (S)-296 in 65% yield and

95:5 er (Scheme 4.43).206

The retention of the enantiomeric ratio proves that the

organolithium intermediate is configurationally stable at −78 °C.

NBoc

SnMe3

H

NBoc

H1. n-BuLi,

THF, _78 °C, 2 h

2. Me2SO4

(S)-295, 95:5 er (S)-29665%, 95:5 er

Scheme 4.43


Pyrrolidine

Our plan to determine the configurational stability of lithiated N-thiopivaloyl

pyrrolidine 210 was to carry out a tin → lithium exchange from an enantioenriched

stannane at −78 °C. First, it was necessary to carry out an asymmetric lithiation of N-

thiopivaloyl pyrrolidine 210 and trapping with benzaldehyde. This would provide a

reaction with which to compare our results from the tin → lithium exchange process.

Therefore, N-thiopivaloyl pyrrolidine 210 was lithiated using s-BuLi/(−)-sparteine in

Et2O for 3 hours at −78 °C. Trapping with benzaldehyde gave diastereomeric alcohols

anti-(S,R)-211 in 40% yield and 86:14 er and syn-(R,R)-211 in 37% yield and 82:18 er

(Scheme 4.44). Conversion into known74

alcohols anti-(S,R)-73and syn-(R,R)-73 by


160

deprotection of the thiopivaloyl group using MeLi and subsequent Boc protection

allowed the assignment of the relative and absolute configuration. It can be concluded

that lithiation-trapping of N-thiopivaloyl pyrrolidine 210 shows the same sense of

induction as the asymmetric lithiation-trapping of N-Boc pyrrolidine 39.38

N

S


Et2O, _78 °C, 3 h

2. PhCHO

N

S

Ph

OH

H

N

S

Ph

OH

H

ant i-(S,R)-211

40%, 86:14 er

syn-(R,R)-211

37%, 82:18 er

NBoc

Ph

OH

H

ant i-(S,R)-73, 50%, 86:14 er

[]D = +79.4 (c 1.0 in CHCl3)

lit.74 []D = +112.7

(for 96:4 er, c 1.5 in CHCl3)

NBoc

Ph

OH

H

syn-(R,R)-73, 70%, 82:18 er[]D = _0.6 (c 0.75 in CHCl3)

lit.74 []D = _1.6

(for 96:4 er, c 1.0 in CHCl3)

1. 6 eq. MeLi, THF,0 °C, 5 h

2. Boc2O, CH2Cl2,rt, 16 h

210 58:42 dr

Scheme 4.44

In addition, stannane (S)-297 was synthesised by lithiation of N-thiopivaloyl pyrrolidine

210 and trapping with trimethyltin chloride in 68% yield and 78:22 er (Scheme 4.45).

The absolute configuration of stannane (S)-297 has not been proved but is assigned by

analogy to the benzaldehyde-trapped products.

N

S


Et2O, _78 °C, 3 h

2. Me3SnCl

N

S

SnMe3

H

(S)-29768%, 78:22 er

210

Scheme 4.45

With stannane (S)-297 in hand, we attempted tin → lithium exchange at −78 °C to

investigate the configurational stability of the lithiated intermediate. Treatment of


161

stannane (S)-297 with n-BuLi in THF at −78 °C followed by trapping with

benzaldehyde gave diastereomeric alcohols anti-rac-211 and syn-rac-211 in 42% yield

and 51:49 er and 52% yield and 51:49 er respectively. Similarly, use of n-

BuLi/TMEDA gave alcohols anti-rac-211 (24%) and syn-rac-211 (66%), each in 50:50

er (Scheme 4.46).

1. n-BuLi,

THF, _78 °C, 5 min

2. PhCHO, _78 °C, 1 h

3. HCl(aq),_78 °C

N

S

SnMe3

H

(S)-297, 78:22 er

N

S

Ph

OH

H

N

S

Ph

OH

H

anti-rac-211

42%, 51:49 er

syn-rac-211

52%, 51:49 er

1. n-BuLi, TMEDA

Et2O, _78 °C, 5 minN

S

SnMe3

H

(S)-297, 78:22 er

N

S

Ph

OH

H

N

S

Ph

OH

H

anti-rac-211

24%, 50:50 er

syn-rac-211

66%, 50:50 er

2. PhCHO, _78 °C, 1 h

3. HCl(aq),_78 °C

40:60 dr

24:76 dr

Scheme 4.46

Remarkably, from these tin → lithium exchange reactions, we conclude that the

lithiated intermediate is configurationally unstable at −78 °C. This is in in contrast with

α-lithiated N-Boc pyrrolidine which is configurationally stable at −78 °C.54,76

By

comparison of lithiated N-thiopivaloyl azetidine to N-thiopivaloyl pyrrolidine we can

conclude that the labile nature of the lithiated intermediates is not due to a decrease in

ring size. Instead, it is suggested that the N-thiopivaloyl protecting group is not as

efficient at stabilising the lithiated intermediate when compared to N-Boc pyrrolidine

39. We speculate that this variation may arise from the difference in bond lengths of the

Boc carbonyl (C=O) and the C=S of the N-thiopivalamide. C=O bonds in carbamates

are typically ca. 1.25 Å in length whereas C=S bonds in thioamides are ca. 1.67 Å

long.211

The longer C=S bond may cause an increase in length of the C-Li bond due to

chelation to the lithium to the sulfur. Thus, a reduction in strength of the C-Li would be

observed making the barrier to enantiomerisation lower (Figure 4.3).


162

N

O O

Li

H

N

S

Li

H

(R)-40 (R)-299

Increased lengthof C-Li bond

~1.25 Å

~1.67 Å

Configurationally Stable at _78 °C Configurationally Unstable at _78 °C

Figure 4.3

4.3.2 Dynamic Resolution of Lithiated N-Thiopivaloyl Pyrrolidine

Since lithiated N-thiopivaloyl pyrrolidine 210 was shown to be configurationally

unstable at −78 °C, an enantioselective deprotonation mechanism can be ruled out.

Therefore, the enantioselectivity observed in the lithiation-trapping of N-thiopivaloyl

pyrrolidine 210 is due to a dynamic resolution process. This means that addition of a

chiral diamine to the racemic organolithium reagent should allow isolation of

enantioenriched products.

Treatment of stannane rac-297 (formed in 76% yield by racemic lithiation-trapping)

with n-BuLi/(−)-sparteine in Et2O at −78 °C for 5 minutes and trapping with

benzaldehyde gave alcohol anti-(S,R)-211 in 39% yield and 88:12 er and syn-(R,R)-211

37% yield and 82:18 er (Scheme 4.47). Importantly, the enantiomeric ratio observed

from the tin → lithium exchange are comparable to those achieved from the asymmetric

lithiation of N-thiopivaloyl pyrrolidine 210 using s-BuLi/(−)-sparteine (see Scheme

4.44).

anti-(S,R)-211 syn-(R,R)-211


Et2O, _78 °C, 5 min

2. PhCHO, _78 °C, 1 h

3. HCl(aq),_78 °C

N

S

SnMe3

rac-297

N

S

Ph

OH

H

N

S

Ph

OH

H

39%, 88:12 er 35%, 82:18 er

55:45 dr

Scheme 4.47

The lithiation of N-thiopivaloyl pyrrolidine 210 was also carried out using (+)-sparteine

surrogate 1 as the ligand. It was hoped that this would allow access to the opposite

enantiomeric series of trapped products in high enantiomer ratio. Indeed, treatment of

N-thiopivaloyl pyrrolidine 210 with s-BuLi/(+)-sparteine surrogate 1 and trapping with


163

benzaldehyde gave alcohol anti-(R,S)-211 in 62% yield and 85:15 er and alcohol syn-

(S,S)-211 in 24% yield and 92:8 er (Scheme 4.48). This is the highest gave the highest

enantioselectivity we have achieved (92:8 er), albeit for the minor diastereoisomer.

N

N



Et2O, _78 °C, 1 hN

S

210

N

S

Ph

OH

H

N

S

Ph

OH

H

ant i-(R,S)-211

62%, 85:15 er

syn-(S,S)-211

24%, 92:8 er

2. PhCHO, _78 °C, 1 h

3. HCl(aq),_78 °C

78:22 dr

H

Scheme 4.48

Finally, methyl iodide was used as the electrophile. Previously, in the lithiation-

trapping of N-thiopivaloyl azetidine 101, methyl iodide had given products with lower

enantiomeric ratio when compared with benzaldehyde (see Scheme 4.36). Lithiation of

N-thiopivaloyl pyrrolidine 210 using s-BuLi/(−)-sparteine and trapping with methyl

iodide gave (S)-298 in 84% yield and 58:42 er (Scheme 4.49). The enantiomeric ratio

of (S)-298 was significantly lower than the products of benzaldehyde-trapping. Thus,

we suggest a dynamic kinetic resolution process is occurring, although further work will

be required to unequivocally establish this. The absolute configuration of the major

enantiomer was assigned by comparison to unpublished work within our group.212

N

S


Et2O, _78 °C, 3 h

2. MeI, _78 °C, 1 h

3. HCl(aq),_78 °C

N

S

H

(S)-29884%, 58:42 er

210

Scheme 4.49


164


Remarkably, lithiated N-thiopivaloyl azetidine and N-thiopivaloyl pyrrolidine have been

shown to be configurationally unstable at −78 °C. This was established by tin →

lithium exchange (n-BuLi, TMEDA, Et2O, −78 °C, 5 min) from stannanes (S)-272

(68:32 er) and (S)-297 (78:22 er) and trapping with benzaldehyde. In both reactions,

products were isolated in 50:50 er (Scheme 4.49). Therefore, we are able to conclude

that a dynamic resolution process is taking place under the asymmetric lithiation

conditions (s-BuLi, chiral diamine, Et2O, −78 °C). Hence, the enantioselectivity

observed in the products does not arise from an enantioselective deprotonation.

1. n-BuLi, TMEDA

Et2O, _78 °C, 5 minN

S

SnMe3

H

(S)-297, 78:22 er

N

S

Ph

OH

H

N

S

Ph

OH

H

ant i-rac-211

24%, 50:50 er

syn-rac-211

66%, 50:50 er

2. PhCHO, _78 °C, 1 h

3. HCl(aq),_78 °C

24:76 dr

N

S

(S)-272, 68:32 er

SnMe3N

S

syn-rac-273

OH

PhH

61%, 50:50 er

N

S

ant i-rac-273

OH

PhH

24%, 50:50 er

1. n-BuLi, TMEDA

Et2O, _78 °C, 5 min

2. PhCHO, _78 °C, 1 h

3. HCl(aq),_78 °C

24:76 dr

Scheme 4.49

The configurational instability of lithiated N-thiopivaloyl azetidine and N-thiopivaloyl

pyrrolidine is in contrast with lithiated N-Boc pyrrolidine and piperidine which are

known to be configurationally stable at −78 °C.52,54,56

Therefore, we conclude that the

configurational instability is due to the thiopivaloyl directing group. We speculate that

this may be due to the increased C=S thioamide bond length when compared to the Boc

carbonyl.

We also found that lithiation of N-thiopivaloyl azetidine 101 using s-BuLi/(−)-sparteine

and trapping with benzaldehyde gave a diastereomeric mixture of alcohols anti-(S,R)-

273 and syn-(R,R)-273. The sense of enantiomeric induction was established by


165

comparison to a sample synthesised with known stereochemistry and was found to be

opposite configuration to that reported in the literature for methyl iodide trapping.102

Similarly, we believe that trapping with methyl iodide gave products with opposite

configuration to that reported by Hodgson and Kloesges (Scheme 4.50). However,

further work is necessary to unequivocally establish the configuration of the methyl

trapped product.

N

S

101

N

S

H

(R)-102, 61:39 er


Et2O, _78 °C, 30 min

2. MeIHodgson:

N

S


Et2O, _78 °C, 30 min

2. PhCHON

S

101 anti-(S,R)-273

N

S

syn-(R,R)-273

OH OH

PhPhH H

9%, 58:42 er 75%, 75:25 er

14:86 dr

Our Results:N

S


Et2O, _78 °C, 30 min

2. MeI

101

N

S

H

(S)-102, 59:41 er

Scheme 4.50

Future work will look to further optimise the asymmetric lithiation-trapping of N-

thiopivaloyl azetidine 101. In particular, the use of alternative chiral ligands will be

explored especially those that have been shown to engender good enantiomeric

induction in dynamic resolution processes of nitrogen heterocycles.52,56

Investigations

will also take place to study the effect of electrophiles on the enantioselectivity of the

lithiation-trapping process.

Furthermore, the Hoffmann test could be used to determine whether the intermediate

organolithium reagents are configurationally unstable on the timescale of trapping (see

Scheme 1.23). Two reactions will be carried out. First, organolithium rac-257 will be

trapped with racemic amide rac-55 to give ketone 299. Second, organolithium rac-257

will be trapped with enantiomerically pure amide (S)-55 to give ketone 299 (Scheme


166

4.51). If the diastereomeric ratios of these two reactions are the same then we can

conclude that a dynamic thermodynamic resolution process is occurring. If the

diastereomeric ratios are different then it can be concluded that a dynamic kinetic

resolution is taking place. Finally, the Hoffman test will also be used to distinguish

between a dynamic thermodynamic and a dynamic kinetic resolution in the asymmetric

lithiation of N-thiopivaloyl pyrrolidine 210.

N

S

Et2O, _78 °C, 30 minN

S

Li

101 rac-257

N

O

MeO NBn2

N

O

MeO NBn2

rac-55

(S)-55

s-BuLi, TMEDAN

S

O

NBn2H

N

S

O

NBn2H

299

299

N

S

Et2O, _78 °C, 30 minN

S

Li

101 rac-257

s-BuLi, TMEDA

Scheme 4.51

Chapter Five: Experimental

167


5.1 General Methods

Water is distilled water. Brine refers to a saturated aqueous solution of NaCl. All non-

aqueous reactions were carried out under oxygen-free Ar using flame-dried glassware.

Alkyllithiums were titrated against N-benzylbenzamide before use.170

All diamines and

electrophiles were distilled over CaH2 before use. Et2O and THF were freshly distilled

from sodium and benzophenone ketyl. Petrol refers to the fraction of petroleum ether

boiling in the range 40-60 C.

Flash column chromatography was carried out using Fluka Chemie GmbH silica (220-

440 mesh). Thin layer chromatography was carried out using Merck F254 aluminium-

backed silica plates. 1H (400 MHz) and

13C (100.6 MHz) NMR spectra were recorded

on a Jeol ECX-400 instrument with an internal deuterium lock. Chemical shifts are

quoted as parts per million and referenced to CHCl3 (H 7.27) and or CDCl3 (C 77.0,

central line of triplet). 13

C NMR spectra were recorded with broadband proton

decoupling. 13

C NMR spectra were assigned using DEPT experiments. Coupling

constants (J) are quoted in Hertz. IR spectra were recorded on an ATI Matteson Genesis

FT-IR spectrometer. Melting points were measured on a Gallenkamp melting point

apparatus. Electrospray high and low resolution mass spectra were recorded on a Bruker

Daltronics microOTOF spectrometer. Chiral stationary phase HPLC was performed on

an Agilent 1200 series instrument and a multiple wavelength, UV/Vis diode array

detector.

The following diamine ligands were made according to the reported procedures: (+)-

sparteine surrogate 119

and diamines (R,R)-42 and (S,S)-42.29


168

5.2 General Procedures

General Procedure A: s-BuLi/diamine-mediated lithiation-electrophilic trapping of

O-alkyl carbamate 14 or O-Alkyl carbamate 125

s-BuLi (0.92 mL of a 1.3 M solution in hexanes, 1.20 mmol, 1.2 eq.) was added

dropwise to a stirred solution of carbamate 14 or 125 (1.00 mmol, 1.0 eq.) and diamine

(1.20 mmol, 1.2 eq.) in Et2O (6 mL) at −78 °C under Ar. The resulting solution was

stirred at −78 °C for 1 h. Then, the electrophile (2.00 mmol, 2.0 eq.) was added

dropwise and the solution was allowed to warm to rt over 2 h and stirred at rt for 16 h.

Saturated NH4Cl(aq) (10 mL) was added and the two layers were separated. The aqueous

layer was extracted with Et2O (3 × 10 mL). The combined organic layers were dried

(Na2SO4) and evaporated under reduced pressure to give the crude product.

General Procedure B: s-BuLi/diamine-mediated lithiation-electrophilic trapping of

O-alkyl carbamate 14 (Quench at −78 °C)


dropwise to a stirred solution of carbamate 14 (263 mg, 1.00 mmol, 1.0 eq.) and

diamine (1.20 mmol, 1.2 eq.) in Et2O (6 mL) at −78 °C under Ar. The resulting solution

was stirred at −78 °C for 1 h. Then, the electrophile (2.00 mmol, 2.0 eq.) was added

dropwise and the solution was stirred at −78 °C for 5 min. Then, MeOH (2 mL) was

added and the resulting solution was allowed to warm to rt over 30 min. The solution

was poured into 1 M HCl(aq) (10 mL) and the two layers were separated. The aqueous


(Na2SO4) and evaporated under reduced pressure to give the crude product.

General Procedure C: s-BuLi/diamine-mediated lithiation-electrophilic trapping of

O-alkyl carbamate 14 with reverse addition to Andersen’s sulfinate (Ss)-97



diamine (1.20 mmol, 1.2 eq.) in Et2O (6 mL) at −78 °C under Ar. The resulting solution

was stirred at −78 °C for 1 h and then added dropwise via cannula transfer to a stirred

solution of Andersen’s sulfinate (Ss)-97 (589 mg, 2.00 mmol, 2.0 eq.) in THF (4 mL) at

−78 °C under Ar. The resulting solution was stirred at −78 °C for 5 min. Then,


169

MeOH(aq) (2 mL) was added and the resulting solution was allowed to warm to rt over

30 min. The solution was poured into 1 M HCl(aq) (10 mL) and the two layers were

separated. The aqueous layer was extracted with Et2O (3 × 10 mL). The combined

organic layers were dried (Na2SO4) and evaporated under reduced pressure to give the

crude product.

General Procedure D: Sulfoxide → Magnesium Exchange Reactions

i-PrMgCl (0.13-0.25 mL of a 2.0 M solution in THF, 0.26-0.50 mmol, 1.3-2.5 eq.) was

added dropwise to a stirred solution of the sulfoxide (0.20 mmol, 1.0 eq.) in THF (8

mL) at rt under Ar. The resulting solution was stirred at rt for 1-30 min. Then, the

electrophile (0.26-0.50 mmol, 1.3-2.5 eq.) was added dropwise and the resulting

solution was stirred at rt for 5 min. Saturated NH4Cl(aq) (7 mL) was added and the two

layers were separated. The aqueous layer was extracted with Et2O (3 × 10 mL). The

combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to

give the crude product.

General Procedure E: s-BuLi-mediated lithiation-electrophilic trapping of N-Boc

pyrrolidine 39 in THF

s-BuLi (1.0 mL of a 1.3 M solution in hexanes, 1.30 mmol, 1.3 eq.) was added dropwise

to a stirred solution of N-Boc pyrrolidine 39 (171 mg, 1.00 mmol, 1.0 eq.) in THF (7

mL) at −78 °C under Ar. The resulting solution was stirred at −78 °C for 1 h. Then, the

electrophile (2.00 mmol, 2.0 eq.) was added dropwise. The solution was allowed to

warm to rt over 2 h and stirred at rt for 16 h. Saturated NH4Cl(aq) (10 mL) was added

and the two layers were separated. The aqueous layer was extracted with Et2O (3 × 15

mL). The combined organic layers were dried (Na2SO4) and evaporated under reduced

pressure to give the crude product.

General Procedure F: s-BuLi/diamine-mediated lithiation-electrophilic trapping of

N-Boc pyrrolidine 39, N-Boc piperidine 48 or N-pivaloyl pyrrolidine 209


to a stirred solution of N-Boc pyrrolidine 39, N-Boc piperidine 48 or N-pivaloyl

pyrrolidine 209 (1.00 mmol, 1.0 eq.) and diamine (1.30 mmol, 1.3 eq.) in Et2O (6 mL)

at −78 °C under Ar. The resulting solution was stirred at −78 °C for 1-3 h. Then, the

electrophile (2.00 mmol, 2.0 eq.) was added dropwise and the solution was allowed to


170

warm to rt over 2 h and stirred at rt for 16 h. Saturated NH4Cl(aq) (10 mL) was added



pressure to give the crude product.

General Procedure G: mCPBA oxidation of α-amino sulfides

mCPBA (208 mg of ~77% purity, 1.20 mmol, 1.1 eq.) was added to a stirred solution of

the sulfide (1.10 mmol, 1.0 eq.) in CH2Cl2 (3 mL) at −40 °C under Ar. The resulting

solution was stirred at −40 °C for 1 h. Then, saturated Na2SO3(aq) (7 mL) and CH2Cl2

(10 mL) were added and the two layers were separated. The aqueous layer was

extracted with CH2Cl2 (2 × 10 mL). The combined organic layers were dried (Na2SO4)

and evaporated under reduced pressure to give the crude product.

General Procedure H: s-BuLi/diamine-mediated lithiation-electrophilic trapping

of N-Boc 4-chloro piperidine 223


dropwise to a stirred solution of N-Boc 4-chloro piperidine 223 (219 mg, 1.0 mmol, 1.0

eq.) and diamine (2.20 mmol, 2.2 eq.) in Et2O (6 mL) at −78 °C under Ar. The resulting

solution was stirred at −78 °C for 1 h. Then, the electrophile (2.20 mmol, 2.2 eq.) was

added dropwise. The solution was allowed to warm to rt over 2 h and stirred at rt for 16

h. Saturated NH4Cl(aq) (10 mL) was added and the two layers were separated. The

aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layers were

dried (Na2SO4) and evaporated under reduced pressure to give the crude product.

General Procedure I: s-BuLi/diamine-mediated lithiation-electrophilic trapping of

N-Boc 4-chloro piperidine 223 (Quench at −78 °C)





added dropwise and the solution was stirred at −78 °C for 5 min. Then, MeOH (2 mL)

was added and the resulting solution was allowed to warm to rt over 30 min. The

solution was poured into 1 M HCl(aq) (10 mL) and the two layers were separated. The


171



General Procedure J: s-BuLi/diamine-mediated lithiation of N-Boc 4-chloro

piperidine 223 with reverse addition to Andersen’s sulfinate (Ss)-97




solution was stirred at −78 °C for 1 h and then added dropwise via cannula transfer to a

stirred solution of Andersen’s sulfinate (Ss)-97 (647 mg, 2.20 mmol, 2.2 eq.) in THF (5

mL) at −78 °C under Ar. The resulting solution was stirred at −78 °C for 5 min. Then,

MeOH (2 mL) was added and the resulting solution was allowed to warm to rt over 30

min. The solution was poured into 1 M HCl(aq) (10 mL) and the two layers were



crude product.

General Procedure K: Sulfoxide → Magnesium Exchange Reactions with

Transmetallation-Negishi Coupling

i-PrMgCl (0.25 mL of a 2.0 M solution in THF, 0.5 mmol, 2.5 eq.) was added dropwise

to a stirred solution of sulfoxide syn-(R,R,SS)-225 (65 mg, 0.20 mmol, 1.0 eq.) in THF

(8 mL) at rt under Ar. The resulting solution was stirred at rt for 1 min. Then, ZnCl2

(0.12 mmol of a 1.0 M solution in Et2O, 0.6 eq.) was added dropwise. The solution was

stirred at rt for 30 min. Then, Pd(OAc)2 (3 mg, 0.01 mmol, 0.05 eq.), t-Bu3PH.BF4 (3.5

mg, 0.012 mmol, 0.06 eq.) and aryl bromide (0.24 mmol, 1.2 eq.) were added

sequentially. The resulting brown solution was stirred at rt for 16 h. Then, NH4OH(aq)

(0.1 mL) was added and the resulting solution was stirred for 30 min. The solids were

removed by filtration through Celite® and the filtrate was washed with water (5 mL).

The organic layer was dried (Na2SO4) and evaporated under reduced pressure to give

the crude product.


172

General Procedure L: s-BuLi/diamine-mediated lithiation-electrophilic trapping of

N-thiopivaloyl azetidine 101


dropwise to a stirred solution of N-thiopivaloyl azetidine 101 (79 mg, 0.50 mmol, 1.0


solution was stirred at −78 °C for 30 min. Then, the electrophile (0.75 mmol, 1.5 eq.)

was added dropwise and the solution was stirred at −78 °C for 1 h. 1 M HCl(aq) (10 mL)

was added and the two layers were separated. The aqueous layer was extracted with

Et2O (3 × 10 mL). The combined organic layers were dried (MgSO4) and evaporated

under reduced pressure to give the crude product.

General Procedure M: s-BuLi/diamine-mediated lithiation-electrophilic trapping

of N-thiopivaloyl pyrrolidine 210


dropwise to a stirred solution of N-thiopivaloyl pyrrolidine 210 (86 mg, 0.50 mmol, 1.0

eq.) and diamine (0.65mmol, 1.3 eq.) in Et2O (5 mL) at −78 °C under Ar. The resulting


added dropwise and the solution was stirred at −78 °C for 1 h. 1 M HCl(aq) (10 mL) was

added and the two layers were separated. The aqueous layer was extracted with Et2O (3

× 10 mL). The combined organic layers were dried (MgSO4) and evaporated under

reduced pressure to give the crude product.


173

5.3 Experimental for Chapter Two

3-Phenylpropyl diisopropylcarbamate 1429

14

O N

O

Ph

3-Phenyl-1-propanol (2.00 g, 14.68 mmol, 1.2 eq.) was added dropwise to a stirred

suspension of NaH (0.70 g of 60% wt in mineral oil, 17.12 mmol, 1.4 eq., prewashed

with 3 × 10 mL Et2O) in Et2O (5 mL) at rt under Ar. The resulting suspension was

stirred at rt for 5 min. Then, a solution of N,N-diisopropylcarbamoyl chloride (2.02 g,

12.22 mmol, 1.0 eq.) in Et2O (16 mL) was added dropwise. The resulting solution was

stirred at rt for 18 h. Then, 2 M HCl(aq) (10 mL) was added and the two layers were


organic layers were washed with 1 M NaOH(aq), dried (2:1 MgSO4/NaHCO3) and

evaporated under reduced pressure to give the crude product as a yellow oil. Purification

by flash column chromatography on silica with 3:2 petrol-Et2O as eluent gave

carbamate 14 (2.82 g, 88%) as a colourless oil, RF (3:2 petrol-Et2O) 0.4; 1

H NMR (400

MHz, CDCl3) δ 7.32-7.27 (m, 2H, Ph), 7.22-7.20 (m, 3H, Ph), 4.21-3.61 (br m, 2H,

NCH), 4.13 (t, J = 6.5 Hz, 2H, OCH2), 2.73 (t, J = 7.5 Hz, 2H, CH2Ph), 2.01-1.97 (m,

2H, CH2), 1.23 (d, J = 7.0 Hz, 12H, NCHMe2); 13

C NMR (100.6 MHz, CDCl3) δ 155.8

(C=O), 141.5 (ipso-Ph), 128.4 (Ph), 128.3 (Ph), 125.9 (Ph), 64.0 (OCH2), 45.7 (NCH),

32.5 (CH2), 30.9 (CH2), 20.9 (Me). Spectroscopic data consistent with those reported in

the literature.213

Lab Book Reference: PJR 1/52A

Methyl p-toluenesulfinate 121

121

SOMe

O

Bromine (4.36 g, 1.40 mL, 27.6 mmol, 3.0 eq.) was added to a stirred suspension of

Na2CO3 (4.87 g, 46.0 mmol, 5.0 eq.) and p-tolyl disulfide (2.27 g, 9.2 mmol, 1.0 eq.) in

MeOH (195 mL) at rt. The resulting yellow suspension was stirred at rt for 3 h during


174

which time the suspension became colourless. Then, the solvent was evaporated under

reduced pressure. CH2Cl2 (100 mL) and water (100 mL) were added to the residue and

the two layers were separated. The aqueous layer was extracted with CH2Cl2 (2 × 50

mL). The combined organic layers were washed with saturated NH4Cl(aq) (50 mL) and

brine (50 mL), dried (Na2SO4) and evaporated under reduced pressure to give the crude

product as a colourless oil. Purification by Kügelrohr distillation gave sulfinate 121

(2.93 g, 93%) as a colourless oil, bp 91-94 °C/2.0 mmHg (lit.,214

129-130 °C/16.0

mmHg); 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.0 Hz, 2H, m-C6H4Me), 7.25 (d, J

= 8.0 Hz, 2H, o-C6H4Me), 3.37 (s, 3H, OMe), 2.34 (s, 3H, Me); 13

C NMR (100.6 MHz,

CDCl3) δ 142.8 (ipso-Ar), 140.7 (ipso-Ar), 129.7 (Ar), 125.3 (Ar), 49.3 (OMe), 21.4

(Me). Spectroscopic data consistent with those reported in the literature.215

(S)-(−)-Menthyl p-toluenesulfinate (SS)-97

(SS)-97

OS

O

Thionyl chloride (46.0 mL, 828 mmol, 4.5 eq.) was added dropwise to a stirred

suspension of sodium p-toluenesulfinate (32.8 g, 184 mmol, 1.0 eq., dried via

azeotropic distillation from 3 x 75 mL toluene) in toluene (110 mL) at 0 °C over 30

min. The resulting solution was stirred at rt for 2 h. Then, the volatiles were

evaporated under reduced pressure and the residue was dissolved in toluene (75 mL).

The volatiles were evaporated under reduced pressure to give the crude sulfinyl

chloride. The crude sulfinyl chloride was dissolved in Et2O (90 mL) and added

dropwise over 30 min to a stirred solution of (−)-menthol (35.9 g, 230 mmol, 1.25 eq.)

in pyridine (33 mL) and Et2O (150 mL) at 0 °C. A white precipitate immediately

formed and the resulting suspension was stirred at rt for 16 h. Then, the suspension was

poured into water (150 mL) and the two layers were separated. The aqueous layer was

extracted with Et2O (2 x 50 mL) and the combined organic layers were washed with 1

M HCl(aq) (3 x 60 mL), dried (Na2SO4) and evaporated under reduced pressure. The

resulting solid was recrystallised from hot acetone (20 mL). A second recrystallisation

of the solid from hot acetone (20 mL) gave Andersen’s sulfinate (SS)-97 (8.65 g, 16%)


175

as colourless needles. Then, 3 drops of conc. HCl(aq) were added to the mother liquor to

effect equilibrium of the sulfinate diastereomers. This resulted in crystallisation of

Andersen’s sulfinate (SS)-97. A recrystallisation of the solid from hot acetone (20 mL)

gave Andersen’s sulfinate (SS)-97 (18.23 g, 34%) as colourless needles. Total yield

from two crops = 26.88 g (50 %) as colourless needles, mp 107-108 °C (lit.,92

mp 107-

109 °C); 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.0 Hz, 2H, m-C6H4Me), 7.33 (d, J

= 8.0 Hz, 2H, o-C6H4Me), 4.13 (td, J = 10.5, 4.5 Hz, 1H, CHOS(O)), 2.42 (s, 3H,

C6H4Me), 2.31-2.26 (m, 1H), 2.14 (dtd, J = 14.0, 7.0, 3.0 Hz, 1H), 1.72-1.66 (m, 2H),

1.50 (m, 1H), 1.36 (ddt, J = 14.0, 10.5, 3.0 Hz, 1H), 1.28-1.24 (m, 1H), 1.10-0.79 (m,

2H), 0.97 (d, J = 8.0 Hz, 3H, Me), 0.87 (d, J = 8.0 Hz, 3H, Me), 0.72 (d, J = 8.0 Hz, 3H,

Me); 13

C NMR (100.6 MHz, CDCl3) δ 143.1 (ipso-Ar), 142.4 (ipso-Ar), 129.6 (Ar),

125.0 (Ar), 80.1 (CHO), 47.8 (CH), 42.9 (CH2), 34.0 (CH2), 31.7 (CH), 25.2 (CH), 23.1

(CH2), 22.1 (Me), 21.5 (Me), 20.8 (Me), 14.4 (Me); [α]D −199.3 (c 1.05 in acetone)

(lit.,92

[α]D −204 (c 2.24 in acetone)). Spectroscopic data consistent with those reported

in the literature.92

(1S)-1-(p-Tolylsulfinyl)-3-phenylpropyl N,N-diisopropylcarbamate anti-(S,Ss)-103

and (1R)-1-(p-tolylsulfinyl)-3-phenylpropyl N,N-diisopropylcarbamate syn-(R,Ss)-

103

(Table 2.1, Entry 1)

syn-(R,Ss)-103

SPh

O H

O

O

iPr2N

ant i-(S,Ss)-103

SPh

O H

O

O

iPr2N

Using general procedure A, s-BuLi (0.92 mL of a 1.3 M solution in hexanes, 1.20

mmol, 1.2 eq.), carbamate 14 (263 mg, 1.00 mmol, 1.0 eq.) and TMEDA (139 mg, 1.20

mmol, 1.2 eq.) in Et2O (5 mL) and a solution of Andersen’s sulfinate (Ss)-97 (382 mg,

1.3 mmol, 1.3 eq.) in THF (1 mL) gave the crude product. Purification by flash column

chromatography on silica with 3:1 petrol-EtOAc + 1% Et3N as eluent gave sulfoxide

anti-(S,Ss)-103 (100 mg, 25%, 83:17 er by CSP-HPLC) as a white solid, mp 58-60 °C;

RF (3:1 petrol-EtOAc) 0.3; IR (CHCl3) 2971, 1697 (C=O), 1436, 1370, 1286, 1091,


176

1035, 910, 812, 731 cm−1

; 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.0 Hz, 2H, m-

C6H4Me), 7.28 (d, J = 8.0 Hz, 2H, o-C6H4Me), 7.21 (t, J = 7.0 Hz, 2H, m-Ph), 7.16 (d, J

= 7.0 Hz, 1H, p-Ph), 7.02 (d, J = 7.0 Hz, 2H, o-Ph), 5.45 (dd, J = 10.0, 3.0 Hz, 1H,

OCH), 3.94 (br s, 2H, NCH), 2.74 (ddd, J = 14.0, 10.0, 5.0 Hz, 1H, PhCHAHB), 2.56

(ddd, J = 14.0, 10.0, 7.0 Hz, 1H, PhCHAHB), 2.40 (s, 3H, Me) 2.36-2.25 (m, 1H, CH),

2.06-1.98 (m, 1H, CH), 1.26 (br s, 12H, NCHMe2); 13

C NMR (100.6 MHz, CDCl3) δ

153.5 (C=O), 141.2 (ipso-Ar), 140.3 (ipso-Ar), 137.4 (ipso-Ar), 129.7 (Ar), 128.3 (Ar),

128.1 (Ar), 126.0 (Ar), 124.4 (Ar), 91.7 (OCH), 46.7 (br, NCH), 46.0 (br, NCH), 31.1

(CH2), 26.0 (CH2), 21.3 (Me), 20.2 (br, Me); MS (ESI) m/z 424 [(M + Na)+, 100], 402

[(M + H)+, 20]; HRMS m/z calcd for C23H31NO3S (M + Na)

+ 424.1917 (+1.3 ppm

error), found 424.1911; CSP-HPLC: Chiracel OD (97.5:2.5 Hexane-iPrOH, 1.0 mL

min-1

) anti-(R,Rs)-103 12.8 min, anti-(S,Ss)-103 14.0 min and sulfoxide syn-(R,Ss)-103

(84 mg, 21%, 85:15 er by CSP-HPLC) as a colourless oil, RF (3:1 petrol-EtOAc) 0.20;

IR (film) 2971, 2968, 1707 (C=O), 1434, 1370, 1291, 1136, 1091, 1038, 809 cm−1

; 1H

NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.0 Hz, 2H, m-C6H4Me), 7.28-7.24 (m, 4H, Ar),

7.21-7.14 (m, 3H, Ar), 5.72 (dd, J = 9.5, 4.0 Hz, 1H, OCH), 3.99 (br s, 1H, NCH), 3.57

(br s, 1H, NCH), 2.79-2.75 (m, 2H, PhCH2), 2.41-2.33 (m, 1H, CH), 2.37 (s, 3H, Me),

2.17-2.08 (m, 1H, CH), 1.21-0.99 (m, 12H, CHMe2); 13


152.3 (C=O), 141.5 (ipso-Ar), 140.3 (ipso-Ar), 136.0 (ipso-Ar), 129.5 (Ar), 128.5 (Ar),

128.4 (Ar), 126.3 (Ar), 125.3 (Ar), 86.8 (OCH), 46.3 (br, NCH) 45.9 (br, NCH), 31.7

(CH2), 30.3 (CH2), 21.3 (Me), 21.1 (Me), 20.8 (Me), 20.2 (Me), 20.1 (Me); MS (ESI)

m/z 424 [(M + Na)+, 90], 402 [(M + H)

+, 100]; HRMS m/z calcd for C23H31NO3S (M +

Na)+ 424.1917, found 424.1905 (+2.7 ppm error); CSP-HPLC: Chiracel OD (97.5:2.5

Hexane-iPrOH, 1.0 mL min-1

) syn-(S,Rs)-103 21.3 min, syn-(R,Ss)-103 23.8 min.


Using general procedure B, s-BuLi (0.92 mL of a 1.3 M solution in hexanes, 1.20





anti-(S,Ss)-103 (93 mg, 23%, 88:12 er by CSP-HPLC) as a white solid, CSP-HPLC:

Chiracel OD (97.5:2.5 Hexane-iPrOH, 1.0 mL min-1

) anti-(R,Rs)-103 12.9 min, anti-

(S,Ss)-103 14.2 min and sulfoxide syn-(R,Ss)-103 (130 mg, 32%, 91:9 er by CSP-HPLC)


177

as a colourless oil, CSP-HPLC: Chiracel OD (97.5:2.5 Hexane-iPrOH, 1.0 mL min-1

)

syn-(S,Rs)-103 22.3 min, syn-(R,Ss)-103 24.5 min.


Using general procedure C, s-BuLi (0.92 mL of a 1.3 M solution in hexanes, 1.20








(S,Ss)-103 14.3 min and sulfoxide syn-(R,Ss)-103 (116 mg, 29%, 90:10 er by CSP-

HPLC) as a colourless oil, CSP-HPLC: Chiracel OD (97.5:2.5 Hexane-iPrOH, 1.0 mL

min-1



Using general procedure B, s-BuLi (0.92 mL of a 1.3M solution in hexanes, 1.20 mmol,

1.2 eq.), carbamate 14 (263 mg, 1.00 mmol, 1.0 eq.) and TMEDA (139 mg, 1.20 mmol,

1.2 eq.) in Et2O (5 mL) and a solution of Andersen’s sulfinate (Ss)-97 (587 mg, 2.0

mmol, 2.0 eq.) in THF (6 mL) gave the crude product. Purification by flash column







)

syn-(S,Rs)-103 21.9 min, syn-(R,Ss)-103 24.2 min and sulfoxide.

Lab Book Reference: PJR 3/224


Using general procedure B, s-BuLi (0.92 mL of a 1.3M solution in hexanes, 1.20 mmol,

1.2 eq.), carbamate 14 (263 mg, 1.00 mmol, 1.0 eq.) and TMEDA (139 mg, 1.20 mmol,

1.2 eq.) in Et2O (5 mL) and a solution of Andersen’s sulfinate (Ss)-97 (882 mg, 3.0

mmol, 3.0 eq.) in THF (8 mL) gave the crude product. Purification by flash column



178






)

syn-(S,Rs)-103 22.0 min, syn-(R,Ss)-103 24.4 min and sulfoxide.





TMEDA (139 mg, 1.20 mmol, 1.2 eq.) in Et2O (5.0 mL) at −78 °C under Ar. The

resulting solution was stirred at −78 °C for 1 h. Then, a freshly prepared solution of

MgBr2 [prepared from 1,2-dibromoethane (0.12 mL, 1.3 mmol) and Mg turnings (50

mg, 1.95 mmol)] in THF was added. Resulting solution is stirred at −78 °C for 1 h and

then a solution of Andersen’s sulfinate (Ss)-97 (382 mg, 2.0 mmol, 2.0 eq.) in THF

(4.0 mL) at −78 °C. The resulting solution was stirred at −78 °C for 5 min. Then,

MeOH (2.0 mL) was added and the resulting solution allowed to warm to rt. The

solution was then poured into sat. NH4Cl(aq) (10 mL) and the two layers were separated.

The aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layers

were dried (Na2SO4) and evaporated under reduced pressure to give the crude product.

Purification by flash column chromatography on silica with 3:1 petrol-EtOAc + 1%

Et3N as eluent gave sulfoxide anti-(S,Ss)-103 (32 mg, 8%, 92:8 er by CSP-HPLC) as a

white solid, CSP-HPLC: Chiracel OD (97.5:2.5 Hexane-iPrOH, 1.0 mL min-1

) anti-

(R,Rs)-103 12.9 min, anti-(S,Ss)-103 13.9 min and sulfoxide syn-(R,Ss)-103 (30 mg, 8%,

87:13 er by CSP-HPLC) as a colourless oil, CSP-HPLC: Chiracel OD (97.5:2.5


) syn-(S,Rs)-103 21.7 min, syn-(R,Ss)-103 23.4 min and

sulfoxide.




mmol, 1.2 eq.), carbamate 14 (395 mg, 1.50 mmol, 1.0 eq.) and (−)-sparteine (422 mg,

1.80 mmol, 1.2 eq.) in Et2O (6 mL) and a solution of Andersen’s sulfinate (Ss)-97 (882


179

mg, 3.0 mmol, 2.0 eq.) in THF (2 mL) gave the crude product. Purification by flash

column chromatography on silica with 3:1 petrol-EtOAc + 1% Et3N as eluent gave

sulfoxide anti-(S,Ss)-103 (319 mg, 53%, 99:1 er by CSP-HPLC) as a white solid, CSP-

HPLC: Chiracel OD (97.5:2.5 Hexane-iPrOH, 1.0 mL min-1

) anti-(R,Rs)-103 13.1 min,

anti-(S,Ss)-103 14.2 min and sulfoxide syn-(R,Ss)-103 (1.5 mg, 0.2%, er not determined)

as a colourless oil.



mmol, 1.2 eq.), carbamate 14 (263 mg, 1.00 mmol, 1.0 eq.) and the (+)-sparteine

surrogate (233 mg, 1.20 mmol, 1.2 eq.) in Et2O (5 mL) and a solution of Andersen’s

sulfinate (Ss)-97 (382 mg, 1.3 mmol, 1.3 eq.) in THF (1 mL) gave the crude product.


Et3N as eluent gave sulfoxide anti-(S,Ss)-103 (32 mg, 7%, 87:13 er by CSP-HPLC) as a

white solid, CSP-HPLC: Chiracel OD (97.5:2.5 Hexane-iPrOH, 1.0 mL min-1

) anti-

(R,Rs)-103 12.7 min, anti-(S,Ss)-103 13.5 min and sulfoxide syn-(R,Ss)-103 (180 mg,

45%, 99:1 er by CSP-HPLC) as a colourless oil, CSP-HPLC: Chiracel OD (97.5:2.5




Using general procedure C, s-BuLi (1.85 mL of a 1.3 M solution in hexanes, 2.4 mmol,

1.2 eq.), carbamate 14 (526 mg, 2.0 mmol, 1.0 eq.) and diamine (S,S)-42 (745 mg, 2.4

mmol, 1.2 eq.) in Et2O (10 mL) and a solution of Andersen’s sulfinate (Ss)-97 (1176

mg, 4.0 mmol, 2.0 eq.) in THF (8 mL) gave the crude product. Purification by flash


sulfoxide anti-(S,Ss)-103 (133 mg, 17%, 95:5 er by CSP-HPLC) as a white solid, [α]D

+27.6 (c 1.0 in CHCl3); CSP-HPLC: Chiracel OD (97.5:2.5 Hexane-iPrOH, 1.0 mL

min-1

) anti-(R,Rs)-103 13.9 min, anti-(S,Ss)-103 15.1 min and sulfoxide syn-(R,Ss)-103

(436 mg, 54%, 99:1 er by CSP-HPLC) as a colourless oil, [α]D +43.7 (c 1.0 in CHCl3);

CSP-HPLC: Chiracel OD (97.5:2.5 Hexane-iPrOH, 1.0 mL min-1

) syn-(S,Rs)-103 25.0

min, syn-(R,Ss)-103 26.6 min.


180


Using general procedure C, s-BuLi (0.92 mL of a 1.3 M solution in hexanes, 1.2 mmol,

1.2 eq.), carbamate 14 (263 mg, 1.0 mmol, 1.0 eq.) and diamine (R,R)-42 (371 mg, 1.2




anti-(S,Ss)-103 (225 mg, 56%, 99:1 er by CSP-HPLC) as a white solid, [α]D +26.9 (c 1.0

in CHCl3); CSP-HPLC: Chiracel OD (97.5:2.5 Hexane-iPrOH, 1.0 mL min-1

) anti-

(R,Rs)-103 13.0 min, anti-(S,Ss)-103 14.0 min and sulfoxide syn-(R,Ss)-103 (56 mg,

14%, 93:7 er by CSP-HPLC) as a colourless oil, [α]D +43.4 (c 0.55 in CHCl3); CSP-

HPLC: Chiracel OD (97.5:2.5 Hexane-iPrOH, 1.0 mL min-1

) syn-(S,Rs)-103 22.1 min,

syn-(R,Ss)-103 24.7 min.

1-(p-Tolylsulfinyl)-3-phenylpropyl N,N-diisopropylcarbamate anti-rac-103 and

syn-rac-103

syn-rac-103

SPh

O H

O

O

iPr2N

ant i-rac-103

SPh

O H

O

O

iPr2N



mmol, 1.2 eq.) in Et2O (6 mL) and methyl p-toluenesulfinate 121 (510 mg, 2.00 mmol,

1.3 eq.) gave the crude product. Purification by flash column chromatography on silica

with 3:1 petrol-EtOAc + 1% Et3N as eluent gave sulfoxide anti-rac-103 (148 mg, 25%)

as a viscous colourless oil and sulfoxide syn-rac-103 (190 mg, 32%) as a colourless oil.

Ethyl diisopropylcarbamate 124123

124

O N

O

Diisopropylamine (8.39 mL, 60 mmol, 3.0 eq.) was added dropwise to a stirred solution

of ethyl chloroformate (1.89 mL, 20 mmol, 1.0 eq.) in CH2Cl2 (20 mL) at 0 °C under


181

Ar. The resulting solution was stirred at 0 °C for 30 min. Then, 1 M HCl(aq) (15 mL)


Et2O (3 × 10 mL). The combined organic layers were dried (MgSO4) and evaporated

under reduced pressure to give the crude product. Purification by flash column

chromatography on silica with 9:1 petrol-Et2O as eluent gave carbamate 124 (3.39 g,

98%) as a colourless oil, RF (9:1 petrol-Et2O) 0.2; 1

H NMR (400 MHz, CDCl3) δ 4.10

(q, J = 7.0 Hz, 2H, OCH2), 4.12-3.62 (m, 2H, NCH), 1.23 (t, J = 7.0 Hz, 3H, OCH2Me),

1.17 (d, J = 6.5 Hz, 12H, NCHMe2); 13

C NMR (100.6 MHz, CDCl3) δ 155.7 (C=O),

60.2 (OCH2), 45.7 (br, NCH), 20.7 (Me), 14.5 (Me). Spectroscopic data consistent with

those reported in the literature.32


(1S)-(p-Tolylsulfinyl)-ethyl N,N-diisopropylcarbamate anti-(S,Ss)-123 and (1R)-(p-

Tolylsulfinyl)-ethyl N,N-diisopropylcarbamate syn-(R,Ss)-123

syn-(R,SS)-123

Me S

O H

O

O

iPr2N

ant i-(S,SS)-123

Me S

O H

O

O

iPr2N


mmol, 1.2 eq.), carbamate 124 (346 mg, 2.00 mmol, 1.0 eq.) and diamine (S,S)-42 (744

mg, 2.40 mmol, 1.2 eq.) in Et2O (12 mL) and a solution of Andersen’s sulfinate (Ss)-97

(1.18 g, 4.0 mmol, 2.0 eq.) in THF (10 mL) gave the crude product. Purification by

flash column chromatography on silica with 3:1 petrol-EtOAc + 1% Et3N as eluent gave

sulfoxide anti-(S,Ss)-123 (24 mg, 4%, er not determined) as a colourless oil, RF (7:3

petrol-EtOAc) 0.4; IR (film) 2971, 2959, 1694 (C=O), 1531, 1475, 1312, 1296, 1050,

910, 854, 732 cm−1

; 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 2H, m-C6H4Me),

7.32 (d, J = 8.0 Hz, 2H, o-C6H4Me), 5.52 (q, J = 6.5 Hz, 1H, OCH), 4.04 (br s, 1H,

NCH), 3.86 (br s, 1H, NCH), 2.40 (s, 3H, Me) 1.36 (d, J = 6.5 Hz, 1H, Me), 1.29-1.21

(br m, 12H, NCHMe2); 13

C NMR (100.6 MHz, CDCl3) δ 153.8 (C=O), 141.2 (ipso-Ar),

137.7 (ipso-Ar), 129.8 (Ar), 124.3 (Ar), 89.3 (OCH), 46.8 (br, NCH), 45.9 (br, NCH),

21.5 (br, Me), 21.4 (Me), 20.3 (br, Me), 9.4 (Me); MS (ESI) m/z 334 [(M + Na)+, 100],

312 [(M + H)+, 80]; HRMS m/z calcd for C16H25NO3S (M + Na)

+ 334.1447, found


182

334.1448 (−0.1 ppm error) and sulfoxide syn-(R,Ss)-123 (55 mg, 9%, er not determined)

as a colourless oil, RF (7:3 petrol-EtOAc) 0.30; IR (film) 2992, 2978, 2970, 1700 (C=O),

1530, 1472, 1450, 1390, 1291, 1122, 1078, 910, 730 cm−1

; 1H NMR (400 MHz, CDCl3)

δ 7.49 (d, J = 8.0 Hz, 2H, m-C6H4Me), 7.29 (d, J = 8.0 Hz, 2H, o-C6H4Me), 5.80 (q, J =

6.5 Hz, 1H, OCH), 3.90 (br s, 1H, NCH), 3.70 (br s, 1H, NCH), 2.39 (s, 3H, Me), 1.48

(d, J = 6.5 Hz, 1H, Me), 1.15-1.04 (m, 12H, CHMe2); 13


152.5 (C=O), 141.7 (ipso-Ar), 136.0 (ipso-Ar), 129.4 (Ar), 125.4 (Ar), 84.0 (OCH),

47.6 (NCH) 46.1 (NCH), 21.5 (Me), 21.4 (Me), 20.8 (Me), 20.5 (Me), 20.1 (Me), 13.7

(Me); MS (ESI) m/z 334 [(M + Na)+, 70], 312 [(M + H)

+, 100]; HRMS m/z calcd for

C16H25NO3S (M + Na)+ 334.1447, found 334.1447 (+0.1 ppm error).

1-(p-Tolylsulfinyl)-ethyl N,N-diisopropylcarbamate anti-rac-123 and 1-(p-

tolylsulfinyl)-ethyl N,N-diisopropylcarbamate syn-rac-123

syn-rac-123

Me S

O H

O

O

iPr2N

ant i-rac-123

Me S

O H

O

O

iPr2N


mmol, 1.2 eq.), carbamate 124 (173 mg, 1.00 mmol, 1.0 eq.) and TMEDA (179 μL, 1.20

mmol, 1.2 eq.) in Et2O (5 mL) and methyl p-tolyl sulfinate 121 (255 mg, 1.5 mmol, 1.5

eq.) gave the crude product. Purification by flash column chromatography on silica

with 3:1 petrol-EtOAc + 1% Et3N as eluent gave sulfoxide anti-rac-123 (90 mg, 29%)

as a colourless oil and sulfoxide syn-rac-123 (69 mg, 22%) as a colourless oil.


183

1-(p-Tolylsulfinyl)-3-phenylpropyl N,N-diisopropylcarbamate anti-rac-103, 1-(p-

tolylsulfinyl)-3-phenylpropyl N,N-diisopropylcarbamate syn-rac-103, 1-(p-

tolylsulfinyl)-ethyl N,N-diisopropylcarbamate anti-rac-123 and 1-(p-tolylsulfinyl)-

ethyl N,N-diisopropylcarbamate syn-rac 123 (Scheme 2.17)

syn-rac-103

SPh

O HpTol

O

O

iPr2N

anti-rac-103

SPh

O HpTol

O

O

iPr2N

syn-rac-123

Me S

O HpTol

O

O

iPr2N

anti-rac-123

Me S

O HpTol

O

O

iPr2N

s-BuLi (0.38 mL of a 1.3 M solution in hexanes, 0.50 mmol, 1.0 eq.) was added to a

stirred solution of carbamate 124 (87 mg, 0.50 mmol, 1.0 eq.) and TMEDA (75 μL, 0.50

mmol, 1.0 eq.) in Et2O (5 mL) at −78 °C under Ar. The resulting solution was stirred at

−78 °C for 1 h. Then, a solution of sulfoxide anti-rac-103 (200 mg, 0.50 mmol, 1.0 eq.)

in Et2O (2 mL) was added dropwise and the resulting solution was stirred at −78 °C for

1 h. MeOH (1 mL) was added and the solution was warmed to rt over 30 min. The

solution was poured into saturated NH4Cl(aq) (10 mL) and the two layers were separated.



Purification by flash column chromatography on silica with 4:1-3:1 petrol-EtOAc + 1%

Et3N as eluent gave recovered carbamate 124 (51 mg, 59%) as a colourless oil and a

70:5:13:12 mixture (by 1H NMR spectroscopy) of sulfoxides anti-rac-103, syn-rac-103,

anti-rac-123, syn-rac-123 (180 mg, 66%, 5%, 13%, 12% respectively based on

sulfoxide anti-rac-103) as a pale yellow oil.

Optimisation of Sulfoxide → Mg Exchange Reaction (Table 2.3)

Methyl 2-[(N,N-diisopropylcarbamoyl)oxy]-4-phenylbutanoate rac-126, O-alkyl

carbamate 14, and i-propyl p-tolyl sulfoxide rac-128


rac-126

Ph

O

OMe

O

O

iPr2NS

pTol

O

rac-128

Ph O NiPr2

O

14


184

Using general procedure D, i-PrMgCl (0.11 mL of a 2.0 M solution in THF, 0.22 mmol,

1.1 eq.) and sulfoxide anti-rac-103 (80 mg, 0.20 mmol, 1.0 eq.) in THF (8 mL) at 0 °C

for 10 s and methyl chloroformate (19 mg, 0.22 mmol, 1.1 eq.) at 0 °C for 5 min gave

the crude product. Purification by flash column chromatography on silica with 9:1

petrol-EtOAc as eluent gave ester rac-126 (31 mg, 49%) as a colourless oil, recovered

sulfoxide anti-rac-103 (16 mg, 20%) and sulfoxide rac-128 (20 mg, 54%) as a

colourless oil.




1.3 eq.) and sulfoxide anti-rac-103 (80 mg, 0.20 mmol, 1.0 eq.) in THF (8 mL) at 0 °C

for 1 min and methyl chloroformate (25 mg, 0.26 mmol, 1.3 eq.) at 0 °C for 5 min gave


petrol-EtOAc as eluent gave ester rac-126 (37 mg, 58%) as a colourless oil, O-alkyl

carbamate 14 (2 mg, 3 %) as a colourless oil, recovered sulfoxide anti-rac-103 (3 mg,

3%) and sulfoxide rac-128 (27 mg, 74%).




1.3 eq.) and sulfoxide anti-rac-103 (80 mg, 0.20 mmol, 1.0 eq.) in THF (8 mL) at rt for

20 s and methyl chloroformate (25 mg, 0.26 mmol, 1.3 eq.) at rt for 5 min gave the

crude product. Purification by flash column chromatography on silica with 9:1 petrol-

EtOAc as eluent gave ester rac-126 (35 mg, 56%) as a colourless oil, O-alkyl carbamate

14 (1 mg, 1%) as a colourless oil, recovered sulfoxide anti-rac-103 (4 mg, 5%) and

sulfoxide rac-128 (26 mg, 71%).





1 min and methyl chloroformate (25 mg, 0.26 mmol, 1.3 eq.) at rt for 5 min gave the



185


















14 (6 mg, 9%) as a colourless oil and sulfoxide rac-128 (31 mg, 84%).







14 (9 mg, 17%) as a colourless oil and sulfoxide rac-128 (30 mg, 82%).




1 min and methyl chloroformate (48 mg, 0.50 mmol, 2.5 eq.) gave the crude product.

Purification by flash column chromatography on silica with 9:1 petrol-EtOAc as eluent


186

gave ester rac-126 (48 mg, 75%) as a colourless oil, O-alkyl carbamate 14 (2.5 mg, 5%)

as a colourless oil and sulfoxide rac-128 (31 mg, 84%).

Methyl (2R)-[N,N-(diisopropylcarbamoyl)oxy]-4-phenylbutanoate (R)-126

(R)-126

Ph

O HOMe

O

O

iPr2N


2.5 eq.) and sulfoxide anti-(S,Ss)-103 (80 mg, 0.20 mmol, 1.0 eq.) in THF (8 mL) and

methyl chloroformate (48 mg, 0.50 mmol, 2.5 eq.) gave the crude product. Purification

by flash column chromatography on silica with 9:1 petrol-EtOAc as eluent gave ester

(R)-126 (46 mg, 73%, 99:1 er by CSP-HPLC) as a colourless oil, RF (9:1 petrol-EtOAc)

0.2; 1

H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 7.5 Hz, 2H, m-Ph), 7.23-7.19 (m, 3H,

Ph), 5.08 (t, J = 6.5 Hz, 1H, OCH), 4.11 (br s, 1H, NCH), 3.80 (br s, 1H, NCH), 3.73 (s,

3H, OMe), 2.79-2.75 (m, 2H, PhCH2), 2.21-2.15 (m, 2H, CH), 1.35-1.20 (br m, 12H,

NCHMe2); 13

C NMR (100.6 MHz, CDCl3) δ 171.6 (CO2Me), 154.8 (i-Pr2NC=O), 140.7

(ipso-Ph), 128.5 (Ph), 128.3 (Ph), 126.2 (Ph), 72.0 (OCH), 52.0 (OMe), 45.4 (br, NCH),

33.3 (CH2), 31.8 (CH2), 20.4 (br, Me); [α]D −17.8 (c 0.55 in CH2Cl2) [lit.127

, [α]D −17.3

(c 1.0 in CH2Cl2) for (R)-126 of 97:3 er)]; CSP-HPLC: Chiracel OD (95:5 Hexane-

iPrOH, 0.5 mL min-1

) (S)-126 10.7 min, (R)-126 11.9 min. Spectroscopic data

consistent with those reported in the literature.127

1-Phenylhex-5-en-(3R)-yl N,N-diisopropylcarbamate (R)-129

(R)-129

Ph

O

O

iPr2N

i-PrMgCl (0.25 mL of a 2.0 M solution in THF, 0.50 mmol, 2.5 eq.) was added

dropwise to a stirred solution of sulfoxide anti-(S,Ss)-103 (80 mg, 0.20 mmol, 1.0 eq.) in

THF (8 mL) at rt under Ar. The resulting solution was stirred at rt for 1 min. Then, a


187

solution of CuBr.SMe2 (8.2 mg, 0.04 mmol, 0.2 eq.) in THF (1.0 mL) and allyl bromide

(43 μL, 0.50 mmol, 2.5 eq.) were added sequentially. The solution was stirred at rt for 2

h. Then, saturated NH4Cl(aq) (10 mL) was added and the two layers were separated.

The aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic layers


Purification by flash column chromatography on silica with 9:1 petrol-Et2O as eluent

gave carbamate (R)-129 (43 mg, 70%, 99:1 er by CSP-HPLC) as a colourless oil, RF

(9:1 petrol-Et2O) 0.3; IR (film) 3047, 2901, 2874, 1654 (C=O), 1597, 1487, 1301,

1298, 1275, 1117, 1054, 893 cm-1

; 1

H NMR (400 MHz, CDCl3) δ 7.29-7.25 (m, 2H,

Ph), 7.19-7.15 (m, 3H, Ph), 5.85-5.76 (m, 1H, CH2=CH), 5.11-5.04 (m, 2H, CH2=CH),

5.00-4.93 (m, 1H, OCH), 4.10 (br s, 1H, NCH), 3.74 (br s, 1H, NCH), 2.74-2.60 (m,

2H, CH), 1.96-1.83 (m, 2H, CH), 1.25-1.21 (br m, 12H, NCHMe2); 13

C NMR (100.6

MHz, CDCl3) δ 155.4 (C=O), 142.0 (ipso-Ph), 134.1 (CH2=CH), 128.4 (Ph), 128.3 (Ph)

125.8 (Ph), 117.5 (CH2=CH), 73.2 (OCH), 46.2 (br, NCH), 39.0 (CH2), 35.9 (CH2),

31.9 (CH2), 20.8 (br, NCHMe2); MS (ESI) m/z 326 [(M + Na)+, 100], 304 [(M + H)

+,

20]; HRMS m/z calcd for C19H29NO2 (M + Na)+ 326.2091, found 326.2082 (+2.5 ppm

error). [α]D +3.0 (c 0.45 in CHCl3); CSP-HPLC: Chiracel OD-H (99:1 Hexane-iPrOH,

1.0 mLmin-1

) (R)-129 5.4 min, (S)-129 6.7 min.

1-Phenylhex-5-en-3-yl N,N-diisopropylcarbamate rac-129

rac-129

Ph

O

O

iPr2N


dropwise to a stirred solution of sulfoxide anti-rac-103 (80 mg, 0.20 mmol, 1.0 eq.) in


solution of CuBr.SMe2 (8.2 mg, 0.04 mmol, 0.2 eq.) in THF (1.0 mL) and allyl bromide

(26 μL, 0.30 mmol, 1.5 eq.) were added sequentially. The solution was stirred at rt for 2

h. Then, saturated NH4Cl(aq) (10 mL) was added and the two layers were separated.

The aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic layers



188


gave carbamate rac-129 (31 mg, 51%) as a colourless oil.

(1R)-(1-Hydroxycyclohexyl)-3-phenylpropyl N,N-diisopropylcarbamate (R)-127

(R)-127

Ph

O

O

iPr2N

OH


2.5 eq.) and sulfoxide anti-(S,Ss)-103 (80 mg, 0.20 mmol, 1.0 eq.) in THF (8 mL) at rt

for 1 min and cyclohexanone (52 μL, 0.50 mmol, 2.5 eq.) gave the crude product.

Purification by flash column chromatography on silica with 95:5 CH2Cl2-Et2O as eluent

gave alcohol (R)-127 (52 mg, 71%, 99:1 er by CSP-HPLC) as a colourless oil, RF (95:5

CH2Cl2-Et2O) 0.2; IR (film) 3392 (OH), 2920, 2889, 1647 (C=O), 1417, 1347, 1278,

1138, 1117, 1034, 894 cm-1

; 1

H NMR (400 MHz, CDCl3) δ 7.30-7.27 (m, 2H, Ph), 7.20-

7.17 (m, 3H, Ph), 4.88-4.81 (m, 1H, OCH), 4.09 (br s, 1H, NCH), 3.87 (br s, 1H, NCH),

2.75-2.58 (m, 2H, CH), 1.98-1.94 (m, 2H, CH), 1.84 (br s, 1H, OH), 1.63-1.25 (br m,

22H, CH + NCHMe2); 13

C NMR (100.6 MHz, CDCl3) δ 155.9 (C=O), 142.1 (ipso-Ph),

128.4 (Ph), 128.3 (Ph) 125.8 (Ph), 80.1 (OCH), 73.2 (COH), 46.5 (br, NCH), 45.4 (br,

NCH), 34.3 (CH2), 33.2 (CH2), 32.7 (CH2), 31.2 (CH2), 25.8 (CH2), 21.8 (br, NCHMe2),

21.5 (CH2), 21.4 (CH2), 20.5 (br, NCHMe2); MS (ESI) m/z 384 [(M + Na)+, 90], 219

(100), 90 (80); HRMS m/z calcd for C22H35NO3 (M + Na)+ 384.2509, found 384.2493

(+4.1 ppm error); [α]D +29.1 (c 0.6 in CHCl3); CSP-HPLC: Chiracel OD (98:2 Hexane-

iPrOH, 0.5 mLmin-1

) (R)-127 14.5 min, (S)-127 21.2 min.





gave alcohol (R)-127 (12 mg, 34%, 98:2 er by CSP-HPLC) as a colourless oil.


189





gave alcohol (R)-127 (8.5 mg, 24%, 98:2 er by CSP-HPLC) as a colourless oil.

(1S)-(1-Hydroxycyclohexyl)-3-phenylpropyl N,N-diisopropylcarbamate (S)-127

and (S)-isopropyl p-tolyl sulfoxide (S)-128

(S)-127

Ph

O

O

iPr2N

OH

S

O

(S)-128


2.5 eq.) and sulfoxide syn-(R,Ss)-103 (96 mg, 0.24 mmol, 1.0 eq.) in THF (9 mL) at rt



gave alcohol (S)-127 (65 mg, 74%, 99:1 er by CSP-HPLC) as a colourless oil, [α]D

−28.6 (c 1.0 in CHCl3); CSP-HPLC: Chiracel OD (98:2 Hexane-iPrOH, 0.5 mLmin-1

)

(R)-127 13.4 min, (S)-127 21.4 min and sulfoxide (S)-128 (31 mg, 78%) as a colourless

oil, RF (95:5 CH2Cl2-Et2O) 0.05; 1

H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.0 Hz, 2H,

m-C6H4Me), 7.31 (d, J = 8.0 Hz, 2H, o-C6H4Me), 2.82 (sept, J = 7.0 Hz, 1H, S(O)CH),

2.82 (s, 3H, Me), 1.19 (d, J = 7.0 Hz, 3H, CHMe), 1.15 (d, J = 7.0 Hz, 3H, CHMe); 13

C

NMR (100.6 MHz, CDCl3) δ 141.5 (ipso-Ar), 138.5 (ipso-Ar), 129.6 (Ar), 125.1 (Ar),

54.6 (CHMe2), 21.5 (Me), 15.8 (Me), 14.2 (Me); [α]D −194.2 (c 1.0 in EtOH) [lit.115

,

[α]D −187 (c 2.4 in EtOH)]. Spectroscopic data consistent with those reported in the

literature.216

The isolation of sulfoxide (S)-128 allows assignment of the configuration in sulfoxides

anti-(S,Ss)-103 and syn-(R,Ss)-103. Sulfoxide (S)-128 is the expected product of double

inversion from Andersen’s sulfinate (SS)-97.


190

1-(1-Hydroxycyclohexyl)-3-phenylpropyl N,N-diisopropylcarbamate rac-127

rac-127

Ph

O

O

iPr2N

OH



1 min and cyclohexanone (52 μL, 0.50 mmol, 2.5 eq.) gave the crude product.


gave alcohol rac-127 (45 mg, 62%) as a colourless oil.

1-Hydroxy-1,4-diphenylbutan-2-yl N,N-diisopropylcarbamate (R,S)-130 and (R,R)-

130

(R,S)-130

Ph

O

O

iPr2N

OH

PhPh

O

O

iPr2N

OH

Ph

(R,R)-130



for 1 min and benzaldehyde (51 μL, 0.50 mmol, 2.5 eq.) gave the crude product which

contained a 90:10 mixture of (R,S)-130 and (R,R)-130 by 1H NMR spectroscopy.

Purification by flash column chromatography on silica with 95:5-9:1 petrol-EtOAc as

eluent gave a 96:4 mixture (by 1H NMR spectroscopy) of alcohols (R,S)-130 and (R,R)-

130 (42 mg, 58%, each diastereoisomer 99:1 er by CSP-HPLC) as a colourless oil, RF

(9:1 petrol-EtOAc) 0.2; IR (film) 3378 (OH), 2923, 2881, 1653 (C=O), 1572, 1451,

1358, 1139, 1118, 943 cm-1 1

H NMR (400 MHz, CDCl3) δ 7.34-7.32 (m, 4H, Ph), 7.28-

7.26 (m, 3H, Ph), 7.21-7.17 (m, 1H, Ph), 7.14-7.12 (m, 2H, Ph), 5.12-5.08 (m, 0.96H,

OCH), 5.06-5.01 (m, 0.04H, OCH), 4.89 (d, J = 3.0 Hz, 1H, CHOH), 3.98-3.81 (m, 2H,

NCH), 2.77-2.70 (m, 1H, PhCHAHB), 2.64-2.57 (m, 1H, PhCHAHB), 1.94-1.88 (m, 2H,

CH), 1.27-1.08 (m, 12H, NCHMe2), OH not resolved; 13

C NMR (100.6 MHz, CDCl3)

for (R,S)-130 δ 156.1 (C=O), 141.4 (ipso-Ph), 140.1 (ipso-Ph), 128.4 (Ph), 128.3 (Ph)


191

128.0 (Ph), 127.5 (Ph), 127.0 (Ph), 126.8 (Ph), 78.6 (OCH), 76.3 (OCH), 46.3 (br,

NCH), 32.4 (CH2), 32.0 (CH2), 20.4 (br, NCHMe2); MS (ESI) m/z 392 [(M + Na)+,

100], 370 [(M + H)+, 35]; HRMS m/z calcd for C19H29NO2 (M + Na)

+ 392.2202, found

392.2202 (+0.3 ppm error), CSP-HPLC: Chiracel OD (95:5 Hexane-iPrOH, 1.0 mLmin-

1) (S,S)-130 14.5 min, (R,S)-130 16.7 min, (R,R)-130 18.6 min, (S,R)-130 26.5 min.

1-Hydroxy-1,4-diphenylbutan-2-yl N,N-diisopropylcarbamate anti-rac-130 and

syn-rac-130

anti-rac-130

Ph

O

O

iPr2N

OH

PhPh

O

O

iPr2N

OH

Ph

syn-rac-130



for 1 min and benzaldehyde (51 μL, 0.50 mmol, 2.5 eq.) gave the crude product which



eluent gave a 92:8 mixture (by 1H NMR spectroscopy) of alcohols (R,S)-130 and (R,R)-

130 (36 mg, 49%) as a colourless oil.

4-Hydroxy-5,5-dimethyl-1-phenylhexan-3-yl N,N-bis(propan-2-yl)carbamate (R,S)-

131 and (R,R)-131

(R,S)-131

Ph

O

O

iPr2N

OH

Ph

O

O

iPr2N

OH

(R,R)-131



for 1 min and pivaldehyde (54 μL, 0.50 mmol, 2.5 eq.) gave the crude product which


Purification by flash column chromatography on silica with 9:1-8:2 petrol-Et2O as


192

eluent gave a 70:30 mixture (by 1H NMR spectroscopy) of alcohols (R,S)-131 and

(R,R)-131 (54 mg, 78%, minor diastereoisomer 99:1 er by CSP-HPLC of the diol, major

diastereoisomer er not determined) as a colourless oil, RF (8:2 petrol-Et2O) 0.2; IR

(film) 3383 (OH), 2914, 2889, 1648 (C=O), 1429, 1300, 1271, 1045 cm-1

; 1

H NMR

(400 MHz, CDCl3) δ 7.31-7.27 (m, 2H, Ph), 7.22-7.17 (m, 3H, Ph), 5.19 (br t, J = 8.0

Hz, 0.3H, OCH), 4.98 (dt, J = 10.0, 2.5 Hz, 0.7H, OCH), 4.04-3.90 (br m, 2H, NCH),

3.48 (d, J = 2.5 Hz, 0.7H, CHOH), 3.24 (d, J = 1.0 Hz, 0.3H, CHOH), 2.78 (ddd, J =

14.0, 10.5, 5.0 Hz, 0.7H, CH), 2.68-2.60 (m, 1.3H, CH), 2.32 (br s, 1H, OH), 2.20-2.10

(m, 1H, CH), 2.00-1.91 (m, 1H, CH), 1.28-1.26 (m, 12H, NCHMe2), 0.96 (s, 6.3H,

CMe3), 0.95 (s, 2.7H, CMe3); 13

C NMR (100.6 MHz, CDCl3) for (R,S)-131 and (R,R)-

131 δ 155.3 (C=O), 154.3 (C=O), 142.0 (ipso-Ph), 141.7 (ipso-Ph), 128.4 (Ph), 128.3

(Ph) 128.3 (Ph), 128.3 (Ph), 125.8 (Ph) 125.8 (Ph), 80.9 (OCH), 79.8 (OCH), 76.2

(OCH), 72.8 (OCH), 46.0 (br, NCH), 45.5 (br, NCH), 35.1 (CMe3), 34.6 (CMe3), 32.41

(CH2), 32.40 (CH2), 32.1 (CH2), 26.6 (CMe3), 26.4 (CMe3) 21.6 (br, NCHMe2), 20.5

(br, NCHMe2); MS (ESI) m/z 372 [(M + Na)+, 100], 350 [(M + H)

+, 50]; HRMS m/z

calcd for C20H34NO3 (M + Na)+ 372.2509, found 372.2496 (+3.4 ppm error).

4-Hydroxy-5,5-dimethyl-1-phenylhexan-3-yl N,N-bis(propan-2-yl)carbamate anti-

rac-131 and syn-rac-131

anti-rac-131

Ph

O

O

iPr2N

OH

Ph

O

O

iPr2N

OH

syn-rac-131


2.5 eq.) and sulfoxide anti-rac-6 (80 mg, 0.20 mmol, 1.0 eq.) in THF (8 mL) at rt for 1

min and pivaldehyde (54 μL, 0.50 mmol, 2.5 eq.) gave the crude product which

contained a 60:40 mixture of anti-rac-19 and syn-rac-19 by 1H NMR spectroscopy.


eluent gave a 70:30 mixture (by 1H NMR spectroscopy) of alcohols anti-rac-19 and

syn-rac-19 (48 mg, 69%) as a colourless oil.


193

(3R,4R)-5,5-Dimethyl-1-phenylhexane-3,4-diol syn-(R,R)-300 and (3R,4S)-5,5-

dimethyl-1-phenylhexane-3,4-diol anti-(R,S)-300

ant i-(R,S)-300

Ph

OH

OH

Ph

OH

OHsyn-(R,R)-300

A 70:30 mixture of alcohols anti-(R,S)-131 and syn-(R,R)-131 (13 mg, 0.037 mmol, 1.0

eq.) in THF (1 mL) was added dropwise to a stirred suspension of LiAlH4 (9 mg, 0.22

mmol, 6.0 eq.) in THF (2 mL) at 0 °C under Ar. The resulting solution was stirred and

heated at 70 °C for 1 h. Then, the solution was cooled to 0 °C and water (1 mL), 2 M

NaOH(aq) (2 mL) and MgSO4 were added sequentially. The solids were removed by

filtration. The filtrate was washed with water (5 mL), dried (MgSO4) and evaporated

under reduced pressure to give the crude product which contained a 70:30 mixture of

anti-(R,S)-300 and syn-(R,R)-300 by 1H NMR spectroscopy. Purification by flash

column chromatography on silica with 4:1-3:1 petrol-EtOAc as eluent gave diol syn-

(R,R)-300 (1.5 mg, 18%, 99:1 er by CSP-HPLC) as a colourless oil, RF (3:1 petrol-

EtOAc) 0.3; 1H NMR (400 MHz, CDCl3) δ 7.32-7.28 (m, 2H, Ph), 7.23-7.18 (m, 3H,

Ph), 3.82 (ddd, J = 8.0, 5.0, 1.0 Hz 1H, CHOH), 3.10 (d, J = 1.0 Hz, 1H, CHOH), 2.80

(ddd, J = 14.0 10.0, 6.0 Hz, 1H, PhCHAHB), 2.70 (ddd, J = 14.0, 9.5, 6.5 Hz, 1H, CH),

1.98 (br s, 2H, OH), 1.93 (dddd, J = 14.0, 9.5, 8.0, 6.0 Hz 1H, CH), 1.80 (dddd, J =

14.0, 10.0, 6.5, 5.0 Hz, 1H, CH), 0.94 (s, 9H, CMe3); 13


141.8 (ipso-Ph), 128.41 (Ph), 128.37 (Ph) 125.9 (Ph), 79.9 (CHOH), 68.9 (CHOH), 38.5

(CH2), 35.0 (CMe3) 32.1 (CH2), 26.2 (CMe3); MS (ESI) m/z 245 [(M + Na)+, 100];

HRMS m/z calcd for C14H22O2 (M + Na)+ 245.1512, found 245.1505 (+2.8 ppm error);

CSP-HPLC: Chiracel AD-H (98:2 Hexane-iPrOH, 1.0 mLmin-1

) (R,R)-300 20.5 min,

(S,S)-300 22.2 min and diol anti-(R,S)-300 (4.5 mg, 55%, er not determined) as a

colourless oil, RF (3:1 petrol-EtOAc) 0.2; 1H NMR (400 MHz, CDCl3) δ 7.32-7.28 (m,

2H, Ph), 7.24-7.17 (m, 3H, Ph), 3.73 (ddd, J = 10.0, 4.0, 3.0 Hz 1H, CHOH), 3.39 (d, J

= 4.0 Hz, CHOH), 2.92 (ddd, J = 14.0 10.0 (9.5), 5.0 Hz, 1H, PhCHAHB), 2.69 (ddd, J =

14.0, 9.5, 7.0 Hz, 1H, CH), 1.96 (dddd, J = 14.0, 9.5, 7.0, 3.0 Hz 1H, CH), 1.89-1.79

(m, 3H, CH + OH), 0.95 (s, 9H, CMe3); 13

C NMR (100.6 MHz, CDCl3) δ 142.1 (ipso-

Ph), 128.5 (Ph), 128.4 (Ph) 125.8 (Ph), 82.8 (CHOH), 72.0 (CHOH), 34.3 (CMe3), 33.9


194

(CH2), 32.2 (CH2), 26.7 (CMe3); MS (ESI) m/z 245 [(M + Na)+, 100]; HRMS m/z calcd

for C14H22O2 (M + Na)+ 245.1512, found 245.1514 (−0.6 ppm error).

5,5-Dimethyl-1-phenylhexane-3,4-diol syn-rac-300 and anti-rac-300

anti-rac-300

Ph

OH

OH

Ph

OH

OHsyn-rac-300

An 80:20 mixture of alcohols anti-rac-131 and syn-rac-131 (90 mg, 0.26 mmol, 1.0 eq.)

in THF (4 mL) was added dropwise to a stirred suspension of LiAlH4 (60 mg, 1.56





under reduced pressure to give the crude product which contained an 80:20 mixture of

anti-rac-300 and syn-rac-300 by 1H NMR spectroscopy. Purification by flash column

chromatography on silica with 4:1-3:1 petrol-EtOAc as eluent gave diol syn-rac-300 (9

mg, 16%) as a colourless oil and diol anti-rac-300 (28 mg, 49%) as a colourless oil

(3R,4S) 4-Hydroxy-5-methyl-1-phenylhexan-3-yl N,N-diisopropylcarbamate (R,S)-

132

(R,S)-132

Ph

O

O

iPr2N

OH



for 1 min and isobutyraldehyde (46 μL, 0.50 mmol, 2.5 eq.) gave the crude product.


eluent gave alcohol (R,S)-132 (46 mg, 70%, 99:1 er by CSP-HPLC) as a colourless oil,

RF (8:2 petrol-Et2O) 0.3; IR (film) 3389 (OH), 2923, 2889, 1648 (C=O), 1418, 1348,


195

1280, 1139, 1118, 1045 cm-1

; 1

H NMR (400 MHz, CDCl3) δ 7.29-7.27 (m, 2H, Ph),

7.20-7.18 (m, 3H, Ph), 4.98 (dt, J = 10.5, 3.5 Hz, 1H, OCH), 4.10-3.89 (br m, 2H,

NCH), 3.48 (dd, J = 7.0, 3.5 Hz, 1H, CHOH), 2.78 (ddd, J = 14.0, 10.5, 5.0 Hz, 1H,

PhCHAHB), 2.64 (ddd, J = 14.0, 10.5, 6.5 Hz, 1H, PhCHAHB), 2.17 (br s, 1H, OH), 2.06

(dtd, J = 14.5, 10.5, 5.0 Hz, 1H, CH), 1.91 (dddd, J = 14.5, 10.5, 6.5, 3.5 Hz, 1H, CH),

1.70 (oct, J = 7.0 Hz, 1H, CHMe2), 1.26 (d, J = 7.0 Hz, 12H, NCHMe2), 0.99 (d, J = 7.0

Hz, 3H, CHMe2), 0.91 (d, J = 7.0 Hz, 3H, CHMe2); 13


155.3 (C=O), 141.9 (ipso-Ph), 128.4 (Ph), 128.3 (Ph) 125.9 (Ph), 78.3 (OCH), 76.1

(CHOH), 46.0 (br, NCH), 32.3 (CH2), 31.0 (CH2), 30.2 (CHMe2), 21.5 (br, NCHMe2),

20.5 (br, NCHMe2), 19.3 (Me), 18.4 (Me); MS (ESI) m/z 358 [(M + Na)+, 100], 336 [(M

+ H)+, 80]; HRMS m/z calcd for C20H34NO3 (M + Na)

+ 358.2353, found 358.2347 (+1.5

ppm error); [α]D +21.22 (c 0.40 in CHCl3); CSP-HPLC: Chiracel OD (95:5 Hexane-

iPrOH, 1.0 mLmin-1

) (R,S)-132 5.8 min, (S,R)-132 7.8 min.

4-Hydroxy-5-methyl-1-phenylhexan-3-yl N,N-diisopropylcarbamate anti-rac-132

anti-rac-132

Ph

O

O

iPr2N

OH



1 min and isobutyraldehyde (46 μL, 0.50 mmol, 2.5 eq.) gave the crude product.


eluent gave alcohol anti-rac-132 (49 mg, 75%) a colourless oil.

4-Hydroxy-1-phenyloctan-3-yl N,N-diisopropylcarbamate (R,S)-133 and (R,R)-133

(R,S)-133

Ph

O

O

iPr2N

OH

Ph

O

O

iPr2N

OH(R,R)-133




196

for 1 min and valeraldehyde (53 μL, 0.50 mmol, 2.5 eq.) gave the crude product which



eluent gave a 90:10 mixture (by 1H NMR spectroscopy) of alcohols (R,S)-133 and

(R,R)-133 (45 mg, 65%, each diastereoisomer 99:1 er by CSP:HPLC) as a colourless

oil, RF (8:2 petrol-Et2O) 0.3; IR (film) 3399 (OH), 2923, 2878, 1647 (C=O), 1428, 1291,

1239, 1117, 1035 cm-1

; 1

H NMR (400 MHz, CDCl3) δ 7.30-7.26 (m, 2H, Ph), 7.20-7.16

(m, 3H, Ph), 4.87 (dt, J = 8.0, 3.5 Hz, 0.9H, OCH), 4.85-4.80 (m, 0.1H, OCH), 4.06 (br

s, 1H, NCH), 3.84 (br s, 1H, NCH), 3.69 (dt, J = 9.0, 3.5 Hz, 0.9H, CHOH), 3.65-3.61

(m, 0.1H, CHOH), 2.79-2.59 (m, 2H, CH), 2.04-1.94 (m, 1H, CH), 1.90-1.81 (m, 1H,

CH), 1.55-1.24 (m, 18H), 0.88 (t, J = 8.0 Hz, 3H, Me); 13


for (R,S)-21 δ 156.2 (C=O), 141.6 (ipso-Ph), 128.4 (Ph), 128.3 (Ph) 126.0 (Ph), 78.6

(OCH), 73.9 (CHOH), 45.6 (br, NCH), 32.5 (CH2), 32.2 (CH2), 32.0 (CH2), 30.2

(CHMe2), 31.9 (CH2), 22.7 (CH2), 20.4 (br, NCHMe2), 14.0 (Me); MS (ESI) m/z 372

[(M + Na)+, 100], 350 [(M + H)

+, 30]; HRMS m/z calcd for C21H35NO3 (M + Na)

+

372.2509, found 372.2493 (+4.3 ppm error); CSP-HPLC: Chiracel OD (99:1 Hexane-

iPrOH, 1.0 mLmin-1

) (R,R)-133 16.8 min, (R,S)-133 19.3 min, (S,S)-133 19.3 min,

(S,R)-133 28.3 min.

4-Hydroxy-1-phenyloctan-3-yl N,N-diisopropylcarbamate anti-rac-133 and syn-

rac-133

ant i-rac-133

Ph

O

O

iPr2N

OH

Ph

O

O

iPr2N

OH

syn-rac-133



1 min and valeraldehyde (53 μL, 0.50 mmol, 2.5 eq.) gave the crude product which



eluent gave a 90:10 mixture (by 1H NMR spectroscopy) of alcohols anti-rac-133 and

syn-rac-133 (37 mg, 53%) as a colourless oil.


197

1-Phenyloctane-3,4-diol anti-rac-134 and syn-rac-134

ant i-rac-134

Ph

OH

OH

Ph

OH

OH

syn-rac-134

A 90:10 mixture of alcohols anti-rac-134 and syn-rac-134 (30 mg, 0.086 mmol, 1.0 eq.)

in THF (1 mL) was added dropwise to a stirred suspension of LiAlH4 (20 mg, 0.52






anti-rac-134 and syn-rac-134 by 1H NMR spectroscopy. Purification by flash column

chromatography on silica with 3:1 petrol-EtOAc as eluent gave a 90:10 mixture (by 1H

NMR spectroscopy) of diols anti-rac-134 and syn-rac-134 (17 mg, 89%) as a colourless

oil, RF (3:1 petrol-EtOAc) 0.2; 1H NMR (400 MHz, CDCl3) δ 7.32-7.28 (m, 2H, Ph),

7.24-7.18 (m, 3H, Ph), 3.65-3.60 (m, 1.8H, CHOH), 3.46-3.44 (m, 0.2H, CHOH), 2.93-

2.83 (m, 1H, CH), 2.76-2.64 (m, 1H, CH), 2.04-1.94 (m, 1H, CH), 1.81-1.77 (m, 5H,

CH + OH), 1.50-1.25 (m, 6H, CH), 0.91 (t, J = 8.0 Hz, 3H, Me); 13

C NMR (100.6 MHz,

CDCl3) for anti-rac-134 δ 142.0 (ipso-Ph), 128.6 (Ph), 128.5 (Ph) 126.2 (Ph), 74.5

(CHOH), 74.0 (CHOH), 32.9 (CH2), 32.4 (CH2), 31.1 (CH2), 28.2 (CH2), 22.8 (CH2),

14.1 (Me). Spectroscopic data for syn-rac-134 consistent with those reported in the

literature.130

This experiment enabled the relative stereochemistry of anti-rac-133 to be

unequivocally established.

Isobutyl boronic acid pinacol ester 301217

301

BO

O


198

Isobutyl boronic acid (1.0 g, 9.90 mmol, 1.0 eq.) was added to a stirred suspension of

pinacol (1.17 g, 9.90 mmol, 1.0 eq.) and MgSO4 (1.78 g, 14.85 mmol, 1.0 eq.) in Et2O

(12 mL) at rt under Ar. The resulting suspension was stirred at rt for 18 h. The

suspension was filtered and the filtrate was evaporated under reduced pressure. The

residue was dissolved in hexane (15 mL), washed with water (3 x 10 mL), dried

(MgSO4) and (100.6 MHz, CDCl3) evaporated under reduced pressure to give the crude

product. Purification by Kügelrohr distillation gave isobutyl boronic acid pinacol ester

301 (1.40 g, 77%) as a colourless oil, bp 52-55 °C/8 mmHg (lit.,217

71 °C/14 mmHg) 1H

NMR (400 MHz, CDCl3) δ 1.84 (nontet, J = 6.5 Hz, 1H, CHMe2), 1.22 (s, 12H, Me),

0.90 (d, J = 6.5 Hz, 6H, CHMe2), 0.71 (d, J = 6.5 Hz, 2H, CH2); 13

C NMR (100.6 MHz,

CDCl3) δ 82.8 (OC), 25.3 (Me), 24.8 (CH2), 24.75 (Me), 15.8 (CH). Spectroscopic data


Lab Book Reference PJR 6/486

(3R)-5-Methyl-1-phenylhexan-3-ol (R)-135

(R)-135

OH




solution of isobutylboronic acid pinacol ester 301 (107 μL, 0.50 mmol, 2.5 eq.) in THF

(1 mL) was added dropwise. The solution was stirred at rt for 30 min and then stirred

and heated at 67 °C for 16 h. The reaction mixture was cooled to 0 °C and 3 M

NaOH(aq) (0.5 mL) and 30 % H2O2(aq) (0.25 mL) were added sequentially. The resulting

solution was stirred at rt for 2 h and then 2 M NaOH(aq) (7 mL) was added. The two

layers were separated and the aqueous layer was extracted with Et2O (3 x 10 mL). The


give the crude product. Purification by flash column chromatography on silica with

95:5-9:1 petrol-EtOAc as eluent gave alcohol (R)-135 (26 mg, 68%, 94:6 er by CSP-

HPLC) as a white solid, mp 44-45 °C (lit.,217

45-47 °C); RF (8:2 petrol-Et2O) 0.3; 1H

NMR (400 MHz, CDCl3) δ 7.32-7.28 (m, 2H, Ph), 7.23-7.18 (m, 3H, Ph), 3.76-3.70 (m,


199

1H, CHOH), 2.81 (ddd, J = 13.5, 10.0, 6.0 Hz, 1H, PhCHAHB), 2.69 (ddd, J = 13.5,

10.0, 6.5 Hz, 1H, PhCHAHB), 1.82-1.68 (m, 3H, PhCH2CH2 + CH), 1.48-1.40 (m, 2H,

CH + OH), 1.30-1.28 (m, 1H, CH), 0.93 (d, J = 8.0 Hz, 3H, CHMe2), 0.91 (d, J = 8.0

Hz, 3H, CHMe2); 13

C NMR (100.6 MHz, CDCl3) δ 142.2 (ipso-Ph), 128.4 (4, Ph), 125.8

(Ph) 69.5 (CHOH), 46.8 (CH2), 39.8 (CH2), 32.2 (CH2), 24.8 (CH or Me), 23.6 (CH or

Me), 22.2 (CH or Me); [α]D +16.0 (c 0.55 in CHCl3) [lit.217

, [α]D +16.00 (c 0.70 in

CHCl3) for (R)-135 of 97:3 er)]; CSP-HPLC: Chiracel OD (98:2 Hexane-iPrOH, 1.0

mLmin-1

) (S)-135 13.4 min, (R)-135 22.2 min. Spectroscopic data consistent with those

reported in the literature.217

n-BuLi (0.23 mL of a 2.2 M solution in hexanes, 0.50 mmol, 2.5 eq.) was added


THF (8 mL) at −78 °C under Ar. The resulting solution was stirred at −78 °C for 1 min.

Then, a solution of isobutylboronic pinacol ester 301 (107 μL, 0.50 mmol, 2.5 eq.) was

added dropwise. The solution was stirred at −78 °C for 30 min and then stirred and

heated at 67 °C for 16 h. The reaction mixture was cooled to 0 °C and 3 M NaOH(aq)

(0.5 mL) and 30 % H2O2(aq) (0.25 mL) were added sequentially. The resulting solution

was stirred at rt for 2 h and then 2 M NaOH(aq) (7 mL) was added. The two layers were

separated and the aqueous layer was extracted with Et2O (3 x 10 mL). The combined



EtOAc as eluent gave alcohol (R)-135 (28 mg, 72%, 99:1 er by CSP-HPLC) as a white

solid, mp 47-48 °C (lit.,217

45-47 °C); [α]D +15.6 (c 0.65 in CHCl3) [lit.,217

[α]D +16.00

(c 0.70 in CHCl3) for (R)-135 of 97:3 er)]; CSP-HPLC: Chiracel OD-H (98:2 Hexane-

iPrOH, 1.0 mLmin-1

) (S)-135 12.9 min, (R)-135 21.4 min. Spectroscopic data consistent

with those reported in the literature.217

5-Methyl-1-phenylhexan-3-ol rac-135

rac-135

OH


200


dropwise to a stirred solution of sulfoxide anti-rac-103 (80 mg, 0.20 mmol, 1.0 eq.) in


solution of isobutylboronic acid pinacol ester 301 (107 μL, 0.50 mmol, 2.5 eq.) in THF

(1 mL) was added dropwise. The solution was stirred at rt for 30 min and then stirred

and heated at 67 °C for 16 h. The reaction mixture was cooled to 0 °C and 3 M

NaOH(aq) (0.5 mL) and 30 % H2O2(aq) (0.25 mL) were added sequentially. The resulting

solution was stirred at rt for 2 h and then 2 M NaOH(aq) (7 mL) was added. The two



give the crude product. Purification by flash column chromatography on silica with

95:5-90:10 petrol-EtOAc as eluent gave alcohol rac-135 (25 mg, 65%) as a white solid.

2-[(4-Methylbenzene)sulfinyl]-4-phenylbutan-2-yl N,N-diisopropylcarbamate 141a

and 141b

141a/141b

SPh

O

CbO Me

n-BuLi (0.31 mL of a 2.5 M solution in hexane, 0.78 mmol, 1.2 eq.) was added

dropwise to a stirred solution of diisopropylamine (110 μL, 0.78 mmol, 1.2 eq.) in THF

(3 mL) at −78 °C under Ar. The resulting solution was warmed to 0 °C over 5 min and

stirred at 0 °C for 15 min. Then, the solution was cooled to −78 °C, stirred at −78 °C

for 10 min and a solution of sulfoxide anti-rac-103 (260 mg, 0.65 mmol, 1.0 eq.) in

THF (7 mL) was added dropwise over 10 min. The resulting solution was stirred at −78

°C for 10 min and MeI (62 μL, 0.98 mmol, 1.5 eq.) was added and the solution was

allowed to warm to rt over 2 h and stirred at rt for 16 h. Then, saturated NH4Cl(aq) (10

mL) was added and the two layers were separated. The aqueous layer was extracted

with Et2O (3 x 10 mL). The combined organic layers were dried (Na2SO4) and

evaporated under reduced pressure to give the crude product. Purification by flash

column chromatography on silica with 98:2-95:5 CH2Cl2-Et2O as eluent gave sulfoxide

141a (132 mg, 49%) as a colourless oil, RF (95:5 CH2Cl2-Et2O) 0.3; IR (film) 2970,

2963, 1693 (C=O), 1541, 1465, 1321, 1296, 1052, 910, 850, 732 cm-1

; 1

H NMR (400


201

MHz, CDCl3) δ 7.57 (d, J = 8.0 Hz, 2H, m-C6H4Me), 7.31-7.20 (m, 7H, Ar), 4.01-3.94

(m, 1H, NCH), 3.78-3.68 (m, 1H, NCH), 3.07 (ddd, J = 14.0, 10.0, 7.0 Hz, 1H,

PhCHAHB), 2.79-2.67 (m, 2H, PhCHAHB + CH), 2.52-2.41 (m, 1H, CH), 2.41 (s, 3H,

C6H4Me), 1.46 (s, 3H, Me), 1.31 (d, J = 6.5 Hz, 3H, NCHMe2), 1.28 (d, J = 6.5 Hz, 3H,

NCHMe2), 1.12 (d, J = 6.5 Hz, 3H, NCHMe2), 0.93 (d, J = 6.5 Hz, 3H, NCHMe2); 13

C

NMR (100.6 MHz, CDCl3) δ 152.5 (C=O), 141.5 (ipso-Ar), 140.9 (ipso-Ar), 136.7

(ipso-Ar), 130.0 (Ar), 129.1 (Ar) 128.5 (Ar), 126.4 (Ar), 124.8 (Ar), 96.6 (OC), 46.4

(br, NCH), 36.0 (CH2), 30.1 (CH2), 21.4 (Me), 20.9 (br, Me), 20.4 (br, Me), 15.5 (Me);

MS (ESI) m/z 438 [(M + Na)+, 100], 416 [(M + H)


C24H33NO3S (M + Na)+ 438.2089, found 438.2089 (+0.0 ppm error) and sulfoxide 141b

(94 mg, 35%) as a colourless oil, RF (95:5 CH2Cl2-Et2O) 0.2; IR (film) 2965, 2959,

1690 (C=O), 1528, 1480, 1450, 1326, 1286, 1052, 912, 732 cm-1

; 1

H NMR (400 MHz,

CDCl3) δ 7.54 (d, J = 8.0 Hz, 2H, m-C6H4Me), 7.29-7.24 (m, 4H, Ar), 7.20 (tt, J = 7.5,

2.0 Hz, 1H, p-Ph), 7.14-7.12 (m, 2H, Ar), 4.05-3.99 (m, 1H, NCH), 3.76-3.70 (m, 1H,

NCH), 2.72-2.59 (m, 2H, CH), 2.39 (s, 3H, C6H4Me), 2.26-2.13 (m, 2H, CH), 1.81 (s,

3H, Me), 1.30 (d, J = 6.5 Hz, 3H, NCHMe2), 1.28 (d, J = 6.5 Hz, 3H, NCHMe2), 1.19

(d, J = 6.5 Hz, 3H, NCHMe2), 1.08 (d, J = 6.5 Hz, 3H, NCHMe2); 13

C NMR (100.6

MHz, CDCl3) δ 152.9 (C=O), 141.5 (ipso-Ar), 141.0 (ipso-Ar), 136.8 (ipso-Ar), 129.3

(Ar), 128.5 (Ar) 128.3 (Ar), 126.2 (Ar), 126.1 (Ar), 96.9 (OC), 46.5 (br, NCH), 46.2

(br, NCH), 32.9 (CH2), 30.0 (CH2), 21.4 (Me), 20.6 (br, Me), 20.4 (br, Me), 18.3 (Me);

MS (ESI) m/z 438 [(M + Na)+, 100], 416 [(M + H)


C24H33NO3S (M + Na)+ 438.2079, found 438.2083 (+0.5 ppm error).


n-BuLi (0.20 mL of a 2.5 M solution in hexane, 0.50 mmol, 1.2 eq.) was added

dropwise to a stirred solution of diisopropylamine (70 μL, 0.50 mmol, 1.2 eq.) in THF

(2 mL) at −78 °C under Ar. The resulting solution was warmed to 0 °C over 5 min and

stirred at 0 °C for 15 min. Then, the solution was cooled to −78 °C, stirred at −78 °C

for 10 min and a solution of sulfoxide anti-rac-103 (170 mg, 0.42 mmol, 1.0 eq.) in

THF (4 mL) was added dropwise over 10 min. The resulting solution was stirred at −78

°C for 10 min and Me2SO4 (59 μL, 0.63 mmol, 1.5 eq.) was added and the solution was

allowed to warm to rt over 2 h and stirred at rt for 16 h. Then, saturated NH4Cl(aq) (10

mL) was added and the two layers were separated. The aqueous layer was extracted

with Et2O (3 x 10 mL). The combined organic layers were dried (Na2SO4) and


202


column chromatography on silica with 98:2-95:5 CH2Cl2-Et2O as eluent gave sulfoxide

141a (94 mg, 54%) as a colourless oil and sulfoxide 141b (49 mg, 28%) as a colourless

oil.

Lab Book Reference 5/374

A solution of sulfoxide anti-rac-103 (170 mg, 0.42 mmol, 1.0 eq.) in THF (4 mL) was

added dropwise over 10 min to a stirred solution of LHMDS (0.50 mL of a 1.0 M

solution in THF, 0.50 mmol, 1.2 eq.) in THF (2 mL) at −78 °C under Ar. The resulting

solution was stirred at −78 °C for 10 min. Then, MeI (40 μL, 0.63 mmol, 1.5 eq.) was

added and the solution was allowed to warm to rt over 2 h and stirred at rt for 16 h.


layer was extracted with Et2O (3 x 10 mL). The combined organic layers were dried

(Na2SO4) and evaporated under reduced pressure to give the crude product. Purification

by flash column chromatography on silica with 98:2-95:5 CH2Cl2-Et2O as eluent gave

sulfoxide 141a (51 mg, 29%) as a colourless oil and sulfoxide 141b (28 mg, 16%) as a

colourless oil.


Attempted synthesis of methyl 2-(diisopropylcarbamoyloxy)-2-methyl-4-

phenylbutanoate rac-142

rac-141a

SPh

O

CbO Me

Ph

Me OCb

OMe

O

1. i-PrMgClTHF, rt, 1 min

2. MeOCOCl

rac-142

S

O

rac-128Not Formed


2.5 eq.) and sulfoxide rac-141a (83 mg, 0.20 mmol, 1.0 eq.) in THF (8 mL) at rt for 1

min and methyl chloroformate (38 μL, 0.50 mmol, 2.5 eq.) gave the crude product. The

1H NMR spectrum of the crude product showed a complex mixture of products.

Sulfoxide rac-141a or sulfoxide rac-128 were not evident. No further purification was

attempted.


203


2.5 eq.) and sulfoxide rac-141a (83 mg, 0.20 mmol, 1.0 eq.) in THF (8 mL) at −78 °C

for 1 min and methyl chloroformate (38 μL, 0.50 mmol, 2.5 eq.) gave the crude product.

The 1H NMR spectrum of the crude product showed a complex mixture of products.

Sulfoxide rac-141a or sulfoxide rac-128 were not evident. No further purification was

attempted.


dropwise to a stirred solution of sulfoxide rac-141a (0.20 mmol, 1.0 eq.) in THF (8 mL)

at −78 °C under Ar. The resulting solution was stirred at −78 °C for 1 min. Then,

methyl chloroformate (38 μL, 0.50 mmol, 2.5 eq.) was added dropwise and the resulting

solution was stirred at −78 °C for 1 h. Saturated NH4Cl(aq) (7 mL) was added and the

two layers were separated. The aqueous layer was extracted with Et2O (3 × 10 mL).

The combined organic layers were dried (Na2SO4) and evaporated under reduced

pressure to give the crude product. The 1H NMR spectrum of the crude product showed

a complex mixture of products and no further purification was attempted.

Attempted synthesis of 1-hydroxy-2-methyl-1,4-diphenylbutan-2-yl

diisopropylcarbamates 143

rac-141a

SPh

O

CbO Me

Ph

Me OCb

Ph

OH

1. i-PrMgCl, THF_78 °C, 1 min

2. PhCHO

rac-143Not Formed



for 1 min and benzaldehyde (50 μL, 0.50 mmol, 2.5 eq.) gave the crude product. The

1H NMR spectrum of the crude product showed a complex mixture of products and no

further purification was attempted.


204

Attempted synthesis of 4-phenylbutan-2-yl diisopropylcarbamate 144

rac-141a

SPh

O

CbO Me

rac-144Not Formed

1. n-BuLi, THF_78 °C, 1 min

2. MeOHPh

Me OCb

H



for 1 min and MeOH (1 mL) gave the crude product. The 1H NMR spectrum of the

crude product showed a complex mixture of products and no further purification was

attempted


dropwise to a stirred solution of sulfoxide rac-141a (0.20 mmol, 1.0 eq.) in THF (8 mL)

at −78 °C under Ar. The resulting solution was stirred at −78 °C for 1 min. Then,

MeOH (1 mL) was added dropwise. Saturated NH4Cl(aq) (7 mL) was added and the two

layers were separated. The aqueous layer was extracted with Et2O (3 × 10 mL). The


give the crude product. The 1H NMR spectrum of the crude product showed a complex

mixture of products and no further purification was attempted.


205

5.4 Experimental for Chapter Three

N-tert-Butoxycarbonyl pyrrolidine 39167

NBoc

39

A solution of di-tert-butyl dicarbonate (2.84 g, 13.0 mmol, 1.0 eq.) in CH2Cl2 (8 mL)

was added to a stirred solution of pyrrolidine (1.17 mL, 14.0 mmol, 1.1 eq.) in CH2Cl2

(15 mL) at 0 °C under Ar. The resulting solution was allowed to warm to rt and stirred

at rt for 3 h. The solvent was evaporated under reduced pressure to give the crude

product. Purification by Kügelrohr distillation gave N-Boc pyrrolidine 39 (2.07 g, 93%)

as a colourless oil, bp 86-92 °C/2.0 mmHg (lit.,167

77-75 °C/0.5 mmHg); 1H NMR (400

MHz, CDCl3) δ 3.28-3.20 (m, 4H, NCH2), 1.80-1.76 (m, 4H,CH2), 1.40 (s, 9H, CMe3);

13C NMR (100.6 MHz, CDCl3) rotamers δ 154.7 (C=O), 78.8 (CMe3), 45.9 (CH2N),

45.6 (CH2N), 28.5 (CMe3), 25.7 (CH2), 24.9 (CH2). Spectroscopic data consistent with



N-tert-Butoxycarbonyl-5-(p-tolylsulfinyl)-2,3-dihydropyrrole 169

N

Boc

S

O

169

Using general procedure E, s-BuLi (1.50 mL of a 1.3 M solution in hexanes, 1.95 mmol,

1.3 eq.) and N-Boc pyrrolidine 39 (257 mg, 1.50 mmol, 1.0 eq.) in THF (6 mL) and

methyl p-toluenesulfinate 121 (510 mg, 3.0 mmol, 2.0 eq.) gave the crude product.


gave dihydropyrrole 169 (145 mg, 31%) as a colourless oil, RF (1:1 petrol-EtOAc) 0.3;

IR (CHCl3) 2980, 1678 (C=O), 1369, 1306, 1153, 1093, 901, 809, 722 cm−1

; 1H NMR

(400 MHz, CDCl3) δ 7.68 (br d, J = 8.0 Hz, 2H, m-C6H4Me), 7.24 (d, J = 8.0 Hz, 2H, o-

C6H4Me), 5.96 (t, J = 3.0 Hz 1H, =CH), 3.97 (br s, 1H, NCH2), 3.85-3.76 (m, 1H,

NCH2), 2.84-2.74 (m, 1H, NCH2CH2), 2.64 (dddd, J = 17.0, 11.5, 6.0, 3.0 Hz, 1H,


206

NCH2CH2), 2.37 (s, 3H, Me), 1.37 (s, 9H, CMe3); 13


rotamers δ 174.3 (C=O), 150.2 (C=O), 142.1 (ipso-Ar), 140.9 (=C)140.8 (=C), 136.5

(Ar), 135.4 (Ar), 130.2 (Ar), 127.7 (Ar), 126.6 (ipso-Ar), 126.2 (ipso-Ar), 124.3 (=CH),

82.7 (CMe3), 46.4 (NCH2), 32.9 (CH2), 28.1 (CMe3), 28.0 (CMe3), 21.5 (br, Me), 17.4

(CH2); (MS (ESI) m/z 330 [(M + Na)+, 100], 208 (40), 238 (100); HRMS (ESI) m/z

calcd for C16H21NO3S (M + Na)+

330.1134, found, 330.1122 (3.7 ppm error).



2.5 eq.) and N-Boc pyrrolidine 39 (171 mg, 1.00 mmol, 1.0 eq.) in THF (6 mL) and

methyl p-toluenesulfinate 121 (510 mg, 3.0 mmol, 3.0 eq.) gave the crude product.


gave dihydropyrrole 169 (136 mg, 44%) as a colourless oil.


N-tert-Butyl piperidine-1-carboxylate 48148

N

Boc

48

Piperidine (7.33 g, 8.50 mL, 68.7 mmol, 1.0 eq.) was added dropwise to a stirred

solution of di-tert-butyl dicarbonate (12.51 g, 57.3 mmol, 0.8) in THF (62.5 mL) at 0 °C

under Ar. The resulting solution was stirred at 0 °C for 10 min and then allowed to

warm to rt and stirred at rt for 1 h. 10% NaHCO3(aq) (70 mL) was added and the mixture

was extracted with Et2O (2 × 150 mL). The combined organic layers were washed with

brine (100 mL), dried (K2CO3) and evaporated under reduced pressure to give the crude

product. Purification by Kügelrohr distillation gave N-Boc piperidine 48 (9.68 g, 64%)


65 °C/1.0 mmHg); 1H NMR (400

MHz, CDCl3) δ 3.30-3.27 (m, 4H, NCH2), 1.51-1.42 (m, 6H, CH2), 1.38 (s, 9H, CMe3).

Spectroscopic data consistent with those reported in the literature.148



207

N-tert-Butylcarbonyl-6-(phenylsulfinyl)-3,4-dihydro-2H-pyridine 171

N

Boc

171

SPh

O

Using general procedure F, s-BuLi (2.50 mL of a 1.3 M solution in hexanes, 3.25 mmol,

1.3 eq.), TMEDA (378 mg, 0.49 mL, 3.25 mmol, 1.3 eq.) and N-Boc piperidine 48 (463

mg, 2.50 mmol, 1.0 eq.) in Et2O (8 mL) at −78 °C for 3 h and methyl benzenesulfinate

170 (624 mg, 4.00 mmol, 1.6 eq.) gave the crude product. Purification by flash column

chromatography on silica with 1:1 petrol-EtOAc as eluent gave tetrahydropyridine 171

(100 mg, 13%) as a colourless oil, RF (1:1 petrol-EtOAc) 0.30; IR (Film) 2975, 1693

(C=O), 1511, 1454, 1391, 1366, 1246, 1166, 1033, 700 cm-1

; 1

H NMR (400 MHz,

CDCl3) δ 7.65 (d, J = 8.0 Hz, 2H, o-Ph), 7.41-4.40 (m, 3H, Ph), 6.37 (t, J = 3.5 Hz, 1H,

=CH), 3.97 (br d, J = 11.5 Hz, 1H, NCHAHB), 2.71 (br s, 1H, NCHAHB), 2.39 (ddt, J =

18.5, 6.5, 3.5 Hz, 1H, =CHCH2), 2.28 (dddd, J = 18.5, 10.0, 7.0, 3.5 Hz, 1H, =CHCH2),

1.86-1.69 (m, 2H, CH2), 1.37 (s, 9H, CMe3); 13

C NMR (100.6 MHz, CDCl3) δ 152.3

(C=O), 144.7 (ipso-Ph), 143.5 (=C) 131.0 (Ph), 128.7 (Ph), 126.4 (Ph), 113.7 (br, =CH),

82.1 (CMe3), 44.9 (NCH2), 28.1 (CMe3), 23.2 (CH2), 22.0 (CH2); MS (ESI) m/z 330

[(M + Na)+, 100], 308 [(M + H)

+, 30], 252 (70); HRMS m/z calcd for C16H21NO3S (M +

Na)+ 330.1134, found 330.1127 (2.2 ppm error).

Lab Book Reference: PJR 1/22C

p-Methoxybenzene disulfide 176218

176

S

MeO

S

OMe

NaBO3.4H2O (2.46 g, 16.0 mmol, 2.0 eq.) was added to a stirred solution of p-

methoxybenzenethiol (1.12 g, 8.0 mmol, 1.0 eq.) in 7:3 MeOH/water (28 mL) at rt. The

resulting solution was stirred at rt for 2 h. Then, water (20 mL) and Et2O (20 mL) were

added and the two layers were separated. The aqueous layer was then extracted with

Et2O (2 × 20 mL). The combined organic layers were washed with brine (30 mL), dried


208

(Na2SO4) and evaporated under reduced pressure to give crude disulfide 176 (1.08 g,

97%) as a colourless oil which was sufficiently pure (by 1H NMR spectroscopy) for

subsequent use, 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.5 Hz, 4H, m-C6H4OMe),

6.85 (d, J = 8.5 Hz, 4H, o-C6H4OMe), 3.81 (s, 3H, OMe); 13

C NMR (100.6 MHz,

CDCl3) δ 160.0 (ipso-C6H4OMe), 132.8 (Ar), 128.5 (ipso-C6H4S), 114.7 (Ar), 55.5

(OMe). Spectroscopic data consistent with those reported in the literature.218


Methyl p-methoxybenzenesulfinate 177119

177

S

MeO

OMe

O

Bromine (0.46 mL, 9.0 mmol, 3.0 eq.) was added to a stirred suspension of Na2CO3

(1.58 g, 15.0 mmol, 5.0 eq.) and p-methoxybenzenedisulfide 176 (832 mg, 3.0 mmol,

1.0 eq.) in MeOH (75 mL) at rt. The resulting yellow suspension was stirred at rt for 3 h

during which time the suspension became colourless. Then, the solvent was evaporated

under reduced pressure. CH2Cl2 (50 mL) and water (50 mL) were added to the residue

and the two layers were separated. The aqueous layer was extracted with CH2Cl2 (2 ×

30 mL). The combined organic layers were washed with saturated NH4Cl(aq) (50 mL)

and brine (50 mL), dried (Na2SO4) and evaporated under reduced pressure to give the

crude product as a colourless oil. Purification by Kügelrohr distillation gave sulfinate

177 (1.05 g, 94%) as a colourless oil, bp 111-116 °C/0.8 mmHg; 1H NMR (400 MHz,

CDCl3) δ 7.60 (d, J = 8.5 Hz, 2H, m-C6H4OMe), 7.00 (d, J = 8.0 Hz, 2H, o-C6H4OMe),

3.84 (s, 3H, C6H4OMe), 3.42 (s, 3H, OMe); 13

C NMR (100.6 MHz, CDCl3) δ 160.1

(ipso-C6H4OMe), 132.9 (Ar), 141.8 (ipso-C6H4S), 114.7 (Ar), 55.6 (OMe).



Attempted synthesis of methyl tert-butylsulfinate 179119

179

SOMe

O

SS

Br2, NaCO3

MeOH, rt, 3 h

178


209

Bromine (1.71 mL, 33.6 mmol, 3.0 eq.) was added to a stirred suspension of Na2CO3

(5.93 g, 56.0 mmol, 5.0 eq.) and t-butyldisulfide 178 (2.00 g, 11.2 mmol, 1.0 eq.) in

MeOH (200 mL) at rt. The resulting yellow suspension was stirred at rt for 3 h during

which time the suspension became colourless. Then, the solvent was evaporated under

reduced pressure. CH2Cl2 (100 mL) and water (100 mL) were added to the residue and

the two layers were separated. The aqueous layer was extracted with CH2Cl2 (2 × 50

mL). The combined organic layers were washed with saturated NH4Cl(aq) (100 mL) and

brine (100 mL), dried (Na2SO4) and evaporated under reduced pressure to give the

crude product as a colourless oil. The 1H NMR spectrum of the crude product showed

only unreacted t-butyldisulfide 179 and no purification was attempted.


(tert-Butyl) 2-methylpropane-2-sulfinothioate 180156

180

SS

O

t-Butyl disulfide 178 (2.00 mL, 12.0 mmol, 1.0 eq.) was added dropwise to a stirred

solution of glacial AcOH (8.30 mL) and 30% H2O2(aq) (1.26 mL, 41.0 mmol, 3.4 eq.) at

0 °C. The resulting solution was stirred at rt for 15 h. Then, the solution was cooled to

0 °C and water (10 mL) and CH2Cl2 (10 mL) were added. The two layers were

separated and the aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The combined

organic layers were washed with saturated NaHSO3(aq) (15 mL), NaHCO3(aq) (3 × 10

mL), and water (15 mL), dried (MgSO4) and evaporated under reduced pressure to give

the crude product as a pale yellow oil. Purification by Kügelrohr distillation gave

sulfinothioate 180 (1.99 g, 85%) as a colourless oil, bp 74-77 °C/2.0 mmHg (lit.,220

70-

71 °C/1.7 mmHg); 1H NMR (400 MHz, CDCl3) δ 1.54 (s, 9H, S(O)CMe3), 1.36 (s, 9H,

SCMe3); 13

C NMR (100.6 MHz, CDCl3) δ 59.4 (CMe3), 48.4 (CMe3), 32.5 (CMe3), 25.1

(CMe3). Spectroscopic data consistent with those reported in the literature.156



210

N-tert-Butylcarbonyl-2-(phenylsulfanyl)pyrrolidine 185

N

Boc

SPh

185


1.3 eq.) and N-Boc pyrrolidine 39 (445 mg, 2.60 mmol, 1.0 eq.) in THF (10 mL) and a

solution of diphenyl disulfide (1.14 g, 5.2 mmol, 2.0 eq.) in THF (2 mL) gave the crude

product. Purification by flash column chromatography on silica with 98:2 CH2Cl2-

acetone as eluent gave sulfide 185 (301 mg, 44%) as a colourless oil, RF (98:2 CH2Cl2-

acetone) 0.7; IR (film) 2976, 2931, 1695 (C=O), 1444, 1406, 1367, 1143, 1078, 1049,

750 cm−1

; 1H NMR (400 MHz, CDCl3) (60:40 mixture of rotamers) δ 7.54-7.42 (m, 2H,

Ph), 7.31-7.29 (m, 3H, Ph), 5.38 (br s, 0.4H, NCH), 5.29-5.27 (m, 0.6H, NCH), 3.51-

3.34 (m, 1.2H, NCH), 3.33-2.22 (m, 0.8H, NCH), 2.20-1.98 (m, 2.4H, CH2CH2), 1.93-

1.83 (m, 1.6H, CH2CH2), 1.44 (s, 3.6H, CMe3), 1.35 (s, 5.4H, CMe3); 13

C NMR (100.6

MHz, CDCl3) δ 153.3 (C=O), 134.4 (ipso-Ph), 133.8 (Ph), 128.7 (Ph), 127.7 (Ph), 79.8

(CMe3), 66.8 (NCH), 45.3 (NCH2), 33.7 (CH2), 28.0 (CMe3), 22.0 (CH2); MS (ESI) m/z

302 [(M + Na)+, 100], 208 (25), 114 (50); HRMS m/z calcd for C15H21NO2S (M + Na)

+

302.1185, found, 302.1181 (+1.4 ppm error).


N-tert-Butylcarbonyl-2-(p-tolylsulfanyl)pyrrolidine 186

N

Boc

S

186


1.3 eq.) and N-Boc pyrrolidine 39 (257 mg, 1.50 mmol, 1.0 eq.) in THF (6 mL) and a

solution of p-tolyl disulfide (739 mg, 3.0 mmol, 2.0 eq.) in THF (2 mL) gave the crude

product. Purification by flash column chromatography on silica with 98:2 CH2Cl2-

acetone as eluent gave sulfide 186 (301 mg, 44%) as a colourless oil, RF (98:2 CH2Cl2-

acetone) 0.40; IR (film) 2974, 2933, 1710 (C=O), 1527, 1390, 1366, 1165 cm

−1;

1H

NMR (400 MHz, CDCl3) (60:40 mixture of rotamers) δ 7.43 (d, J = 7.5 Hz, 0.8H, o-


211

C6H4Me), 7.38 (d, J = 7.5 Hz, 1.2H, o-C6H4Me), 7.12 (d, J = 7.5 Hz, 2H, m-C6H4Me),

5.32 (br s, 0.4H, NCH), 5.22 (br d, J = 5.5 Hz, 0.6H, NCH), 3.46-3.39 (m, 1.2H, NCH),

3.30-3.27 (m, 0.8H, NCH), 2.34 (s, 3H, Me), 2.21-2.03 (m, 2.4H, CH2CH2), 2.01-1.86

(m, 1.6H, CH2CH2), 1.45 (s, 3.6H, CMe3), 1.36 (s, 5.4H, CMe3); 13

C NMR (100.6 MHz,

CDCl3) δ 153.7 (C=O), 138.3 (ipso-Ar), 135.1 (Ar), 130.3 (ipso-Ar), 129.8 (Ar), 80.1

(CMe3), 67.1 (NCH), 45.6 (NCH2), 33.8 (CH2), 32.5 (CH2), 28.5 (CMe3), 21.3 (Me);

MS (ESI) m/z 316 [(M + Na)+, 100]; HRMS m/z calcd for C16H23NO2S (M + Na)

+

316.1342, found 316.1342 (0.0 ppm error).

Lab Book Reference: PJR 1/35B

N-tert-Butylcarbonyl-2-(p-methoxyphenylsulfanyl)pyrrolidine 187

N

Boc

S

187

OMe


1.3 eq.) and N-Boc pyrrolidine 39 (257 mg, 1.50 mmol, 1.0 eq.) in THF (6 mL) and p-

methoxyphenyldisulfide 176 (745 mg, 3.0 mmol, 2.0 eq.) gave the crude product.


gave sulfide 187 (65 mg, 14%) as a colourless oil, RF (98:2 CH2Cl2-Et2O) 0.30; 1H

NMR (400 MHz, CDCl3) (60:40 mixture of rotamers) δ 7.48 (d, J = 8.0 Hz, 0.8H, o-

C6H4OMe), 7.42 (d, J = 8.0 Hz, 1.2H, o-C6H4OMe), 6.84 (d, J = 8.0 Hz, 2H, m-

C6H4OMe), 5.25 (br s, 0.4H, NCH), 5.16 (br d, J = 6.0 Hz, 0.6H, NCH), 3.80 (s, 3H,

C6H4OMe), 3.45-3.28 (m, 2H, NCH), 2.14-1.99 (m, 2.4H, CH), 1.89-1.81 (m, 1.6H,

CH), 1.43 (s, 3.6H, CMe3), 1.36 (s, 5.4H, CMe3; MS (ESI) m/z 332 [(M + Na)+, 100];

HRMS m/z calcd for C16H23NO3S (M + Na)+ 332.1291, found 332.1289 (+0.5 ppm

error).



212

N-tert-Butylcarbonyl-2-(tert-butylsulfanyl)pyrrolidine 184

N

Boc

S

184


1.3 eq.) and N-Boc pyrrolidine 39 (257 mg, 1.50 mmol, 1.0 eq.) in THF (6 mL) and p-

tolyldisulfide 178 (535 mg, 3.0 mmol, 2.0 eq) gave the crude product. Purification by

flash column chromatography on silica with 4:1 petrol-Et2O as eluent gave sulfide 184

(230 mg, 59%) as a colourless oil, RF (4:1 petrol-Et2O) 0.40; IR (film) 2979, 1689

(C=O), 1393, 1367, 1254, 1163, 1117, 1042, 921, 870 cm−1

; 1H NMR (400 MHz,

CDCl3) (50:50 mixture of rotamers) δ 5.22 (br s, 0.5H, NCH), 5.03 (br s, 0.5H, NCH),

3.39-3.34 (m, 1H, NCH), 3.30-3.22 (m, 1H, NCH), 2.20-2.03 (m, 2H, CH), 1.99-1.85

(m, 2H, CH), 1.44 (br s, 9H, CMe3), 1.38 (br s, 9H, CMe3); 13

C NMR (100.6 MHz,

CDCl3) δ 153.4 (C=O), 82.7 (CMe3), 79.4 (CMe3), 60.7 (NCH), 45.3 (br, NCH2), 43.5

(br, NCH2), 36.6 (CH2), 35.6 (CH2), 31.5 (CMe3), 28.5 (CMe3); MS (ESI) m/z 282 [(M

+ Na)+, 90], 210 (50), 114 (100); HRMS m/z calcd for C13H25NO2S (M + Na)

+

282.1498, found 282.1477 (+7.7 ppm error).



1.3 eq.) and N-Boc pyrrolidine 39 (257 mg, 1.50 mmol, 1.0 eq.) in THF (6 mL) and t-

butylsulfinothioate 180 (582 mg, 3.0 mmol, 2.0 eq.) gave the crude product.


gave sulfide 184 (60 mg, 15%) as a colourless oil.


N-tert-Butylcarbonyl-2-(phenylsulfanyl)piperidine 151

N

Boc

151

SPh


213


1.3 eq.), TMEDA (378 mg, 0.49 mL, 3.25 mmol, 1.3 eq.) and N-Boc piperidine 48 (463

mg, 2.50 mmol, 1.0 eq.) in Et2O (8 mL) at −78 °C for 3 h and a solution of diphenyl

disulfide (1.36 g, 6.25 mmol, 2.5 eq.) in Et2O (3 mL) gave the crude product.

Purification by flash column chromatography on silica with 98:2 CH2Cl2-acetone as

eluent gave sulfide 151 (460 mg, 63%) as a colourless oil, RF (98:2 CH2Cl2-acetone)

0.5; 1

H NMR (400 MHz, CDCl3) (65:35 mixture of rotamers) δ 7.49 (br s, 2H, Ph), 7.29

(br s, 3H, Ph), 6.05 (br s, 0.35H, NCH), 5.79 (br s, 0.65H, NCH), 4.07 (br d, J = 11.5

Hz, 0.65H, NCH), 3.86 (br s, 0.35H, NCH), 3.29 (td, J = 13.0, 3.0 Hz, 1H, NCH), 1.98-

1.49 (m, 6H, CH), 1.30 (s, 3.15H, CMe3), 1.15 (s, 6.85H, CMe3); 13

C NMR (100.6

MHz, CDCl3) rotamers δ 153.8 (C=O), 135.1 (ipso-Ar), 133.9 (br, Ar), 129.4 (Ar),

129.0 (Ar), 128.9 (br, Ar), 128.0 (br, Ar), 125.7 (Ar), 79.8 (CMe3), 64.1 (br, NCH), 61.7

(br, NCH), 39.4 (br, NCH2), 38.0 (br, NCH2), 31.2 (br, CH2), 30.2 (br, CH2), 28.3

(CMe3), 27.9 (br, CH2), 25.4 (CH2), 19.8 (CH2). Spectroscopic data consistent with


Lab Book Reference: PJR 1/25C

N-tert-Butyl carbonyl-2-hydroxypyrrolidine 175

(Table 3.1, entry 1)

N

Boc

175

OH

mCPBA (77 mg of ~77% purity, 0.35 mmol, 1.0 eq) was added dropwise to a stirred

solution of phenylsulfanyl pyrrolidine 185 (100 mg, 0.35 mmol, 1.0 eq.) and Na2CO3

(80 mg, 0.74 mmol, 2.1 eq.) in CH2Cl2 (5 mL) at rt under Ar. The resulting solution

was stirred at rt for 30 min. Then, saturated Na2SO3(aq) (7 mL) and CH2Cl2 (7 mL) was

added. The two layers were separated and the aqueous layer was extracted with CH2Cl2

(3 × 7 mL). The combined organic layers were dried (Na2SO4) and evaporated under

reduced pressure to give the crude product. Purification by flash column

chromatography on silica with 9:1 CH2Cl2-aceteone as eluent gave recovered sulfanyl

pyrrolidine 185 (26 mg, 26%) as a colourless oil and hydroxy pyrrolidine 175 (21 mg,

31%) as a colourless oil, RF (9:1 CH2Cl2-acetone) 0.3; IR (Film) 3452 (OH), 2976, 1695


214

(C=O), 1478, 1392, 1254, 1163, 1112, 1041, 916 cm−1

; 1

H NMR (400 MHz, CDCl3)

(60:40 mixture of rotamers) δ 5.48 (br s, 0.6H, NCH), 5.39 (br m, 0.4H, NCH), 3.56-

3.46 (m, 1H, NCH), 3.34-3.17 (m, 1H, NCH), 2.11-1.78 (m, 4H, CH), 1.50 (s, 3.6H,

CMe3), 1.47 (s, 5.4H, CMe3); 13

C NMR (100.6 MHz, CDCl3) δ 155.3 (C=O), 81.5

(NCHOH), 80.0 (CMe3), 45.9 (NCH2), 32.6 (CH2), 28.4 (CMe3), 22.7 (CH2); MS (ESI)

m/z 379 [(M Dimer + Na)+, 100], 266 (50), 210 [(M + Na)


C9H17NO3 (M + Na)+ 210.1101, found 210.101 (−0.1 ppm error). Spectroscopic data




mCPBA (89 mg of ~77% purity, 0.41 mmol, 1.1 eq) was added to a stirred solution of

KF (40 mg, 0.69 mmol, 1.8 eq.) in 4:1 MeCN-water (3 mL) at 0 °C. The resulting

solution was stirred at 0 °C for 30 min. Then, phenylsulfanyl pyrrolidine 185 (107 mg,

0.38 mmol, 1.0 eq.) was added. The resulting solution was stirred at 0 °C for 30 min.

Then, saturated Na2SO3(aq) (7 mL) and Et2O (7 mL) was added. The two layers were

separated and the aqueous layer was extracted with Et2O (3 × 7 mL). The combined


crude product. Purification by flash column chromatography on silica with 9:1 CH2Cl2-

acetone as eluent gave hydroxy pyrrolidine 175 (40 mg, 57%) as a colourless oil.



Using general procedure G, mCPBA (208 mg of ~77% purity, 1.20 mmol, 1.1 eq.) and

phenylsulfanyl pyrrolidine 185 (309 mg, 1.10 mmol, 1.0 eq.) in CH2Cl2 (2.2 mL) gave


CH2Cl2-acetone as eluent gave hydroxy pyrrolidine 175 (179 mg, 86%) as a colourless

oil.




p-tolylsulfanyl pyrrolidine 186 (140 mg, 0.47 mmol, 1.0 eq.) in CH2Cl2 (1.5 mL) gave



215

CH2Cl2-acetone as eluent gave hydroxy pyrrolidine 175 (72 mg, 81%) as a colourless

oil.



Using general procedure G, mCPBA (47 mg of ~77% purity, 0.21 mmol, 1.1 eq.) and p-

methoxyphenylsulfanyl pyrrolidine 187 (60 mg, 0.19 mmol, 1.0 eq.) in CH2Cl2 (1.0

mL) gave the crude product. Purification by flash column chromatography on silica

with 3:2 petrol-EtOAc as eluent gave hydroxy pyrrolidine 175 (27 mg, 74%) as a

colourless oil.




t-butylsulfanyl 184 (120 mg, 0.46 mmol, 1.0 eq.) in CH2Cl2 (1.5 mL) gave the crude

product. Purification by flash column chromatography on silica with 7:3 petrol-EtOAc

as eluent gave hydroxy pyrrolidine 175 (65 mg, 77%) as a colourless oil.



H2O2 (0.07 mL of a 30% aqueous solution, 0.61 mmol, 1.8 eq.) was added dropwise to a

stirred solution of sulfanyl pyrrolidine 186 (100 mg, 0.34 mmol, 1.0 eq.) in

hexafluoroisopropanol (0.7 mL) at rt under Ar. The resulting solution was stirred at rt

for 10 min. Then, saturated Na2SO3(aq) (5 mL) and Et2O (5 mL) was added. The two

layers were separated and the aqueous layer was extracted with Et2O (3 × 5 mL). The


give the crude product. Purification by flash column chromatography on silica with 9:1

CH2Cl2-aceteone as eluent gave recovered sulfanyl pyrrolidine 186 (42 mg, 42%) and

hydroxy pyrrolidine 175 (26 mg, 43%) as a colourless oil.




dropwise to a stirred solution of N-Boc pyrrolidine 39 (257 mg, 1.50 mmol, 1.0 eq.) in


216

THF (6 mL) at −78 °C under Ar. The resulting solution was stirred at −78 °C for 1 h

and then added dropwise via cannula transfer to methyl p-toluenesulfinate 121 (765 mg,

4.50 mmol, 3.0 eq.) at 0 °C under Ar. The resulting solution was stirred at 0 °C for 15

min. Then, saturated NH4Cl(aq) (7 mL) was added and the two layers were separated.


were dried (MgSO4) and evaporated under reduced pressure to give the crude product.


eluent gave dihydropyrrole 169 (45 mg, 10%) and hydroxy pyrrolidine 175 (142 mg,

52%) as a colourless oil.



dropwise to a stirred solution of N-Boc pyrrolidine 39 (257 mg, 1.50 mmol, 1.0 eq.) in

THF (6 mL) at −78 °C under Ar. The resulting solution was stirred at −78 °C for 1 h

and then added dropwise via cannula transfer to methyl p-toluenesulfinate 121 (765 mg,

4.50 mmol, 3.0 eq.) at 0 °C under Ar. The resulting solution was stirred at 0 °C for 15

min. Then, saturated NH4Cl(aq) (7 mL) was added and the two layers were separated.




eluent gave hydroxy pyrrolidine 175 (135 mg, 48%) as a colourless oil.


2,2,2-Triphenyl-1-pyrrolidin-1-ylethanone 207

207

N

OPh3C

Thionyl chloride (3.0 mL, 15.4 mmol, 1.5 eq.) was added to a stirred solution of

triphenylacetic acid (2.97 g, 10.3 mmol, 1.0 eq.) in THF (30 mL) at room temperature

under Ar. The resulting solution was heated at 70 °C and for 3 h. Then, the solution

was allowed to cool to rt. The solvent was evaporated under reduced pressure to give

the crude acid chloride (3.51 g) as a brown solid (3.51 g). To a stirred solution of the


217

crude acid chloride in THF (20 mL) at 0 °C, pyridine (0.90 mL, 12.5 mmol, 1.2 eq.) and

pyrrolidine (0.85 mL, 10.3 mmol, 1.0 eq.) were added. The resulting solution was

heated at 70 °C for 16 h. The solution was allowed to cool to rt and then saturated

NH4Cl(aq) (30 mL) was added. The two layers were separated and the aqueous layer

was extracted with Et2O (3 × 25 mL). The combined organic layers were dried

(Na2SO4) and evaporated under reduced pressure to give the crude product as yellow

solid. Purification by flash column chromatography on silica with 7:3 petrol-EtOAc as

eluent gave amide 207 (3.01 g, 86%) as a white solid, mp 186-189 °C (lit.,221

188.5 °C);

RF (7:3 petrol-EtOAc) 0.3; 1H NMR (400 MHz, CDCl3) δ 7.31-7.21 (m, 15H, Ph), 3.68

(t, J = 7.0, 2H, NCH2), 2.46 (t, J = 7.0, 2H, NCH2), 1.71 (quintet, J = 7.0, 2H, CH2),

1.57 (quintet, J = 7.0, 2H, CH2); 13

C NMR (100.6 MHz, CDCl3) δ 170.7 (C=O), 142.9

(ipso-Ph), 130.5 (Ph), 127.7 (Ph), 126.6 (Ph), 54.8 (CPh3), 48.3 (NCH2), 26.6 (CH2).



2,2-Dimethyl-1-pyrrolidin-1-yl-propanone 209

N

209

O

Trimethylacetyl chloride (3.87 g, 32.0 mmol, 1.0 eq.) was added to a stirred solution of

pyridine (4.30 mL, 54.0 mmol, 1.7 eq.) and pyrrolidine (2.89 mL, 32.0 mmol, 1.0 eq.) in

CHCl3 (28 mL) at 0 °C. The resulting solution was heated at 65 °C and stirred for 16 h.

The solution was allowed to cool to rt and then water (50 mL) was added. The two

layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL).

The combined organic layers were dried (MgSO4) and evaporated under reduced

pressure to give the crude product as a yellow solid. Recrystallisation from CHCl3 gave

amide 209 (5.09 g, 100%) as colourless needles, mp 53-56 °C (lit.,222

56-59 °C); 1H

NMR (400 MHz, CDCl3) δ 3.54 (br s, 4H, NCH2), 1.86 (br s, 4H, CH2), 1.25 (s, 9H,

CMe3); 13

C NMR (100.6 MHz, CDCl3) δ 176.4 (C=O), 47.8 (NCH2), 38.9 (CMe3), 27.5

(CMe3), 23.0 (CH2). Spectroscopic data consistent with those reported in the

literature.223



218

1-(Toluene-4-sulfinyl)pyrrolidine 208

N

S

208

O


1.3 eq.), (−)-sparteine (396 mg, 1.69 mmol, 1.3 eq.) and amide 207 (208 mg, 1.30

mmol, 1.0 eq.) in Et2O (5 mL) at −78 °C for 3 h and methyl p-toluenesulfinate 121 (443

mg, 2.60 mmol, 2.0 eq.) gave the crude product. Purification by flash column

chromatography on silica with 1:1 petrol-EtOAc as eluent gave sulfinamide 208 (171

mg, 64%) as a colourless oil, RF (1:1 petrol-EtOAc) 0.3; 1

H NMR (400 MHz, CDCl3) δ

7.50 (d, J = 8.0 Hz, 2H, m-C6H4Me), 7.23 (d, J = 8.0 Hz, 2H, o-C6H4Me), 3.33-3.26 (m,

2H, NCH2), 2.98-2.92 (m, 2H, NCH2), 2.35 (s, 3H, Me), 1.82-1.76 (m, 4H, CH2); 13

C

NMR (100.6 MHz, CDCl3) δ 141.4 (ipso-Ar), 140.7 (ipso-Ar), 129.4 (Ar), 125.7 (Ar),

45.9 (NCH2), 25.9 (CH2), 21.3 (Me). Spectroscopic data consistent with those reported

in the literature.224



dropwise to a stirred solution of triphenylacetamide 209 (512 mg, 1.50 mmol, 1.0 eq.) in

THF (15 mL) at −40 °C under Ar. The resulting solution was stirred at −40 °C for 3 h.

Then, methyl p-toluenesulfinate 121 (255 mg, 1.5 mmol, 1.0 eq.) was added dropwise.

The resulting solution was stirred at −40 °C for 1 h. Saturated NH4Cl(aq) (10 mL) was

added and the two layers were separated. The aqueous layer was extracted with Et2O (3

× 15 mL). The combined organic layers were dried (Na2SO4) and evaporated under


chromatography on silica with 1:1 petrol-EtOAc as eluent gave sulfinamide 208 (83 mg,

31%) as a colourless oil,



219

Attempted synthesis of 1-[2-(p-tolylsulfinyl)pyrrolidin-1-yl]-2,2-dimethyl-

propanthione 191

N

191

S

S

O

N

210

S

1. s-BuLi/TMEDA

Et2O, _78 °C, 3 h

2. pTolS(O)OMe, 18 h

Using general procedure M, s-BuLi (1.50 mL of a 1.3 M solution in hexanes, 1.95

mmol, 1.3 eq.), TMEDA (227 mg, 1.95 mmol, 1.3 eq.) and thioamide 210 (257 mg,

1.50 mmol, 1.0 eq.) in Et2O (6 mL) at −78 °C for 3 h and methyl p-toluenesulfinate 191

(510 mg, 3.0 mmol, 2.0 eq.) gave the crude product which contained none of the desired

product by 1H NMR spectroscopy. Purification by flash column chromatography on

silica with 4:1 petrol-Et2O as eluent gave starting thioamide 210 (151 mg, 59%) as pale

yellow needles.


Attempted synthesis of 1-[2-(p-tolylsulfanyl)pyrrolidin-1-yl]-2,2-dimethyl-

propanthione 213

N

210

S

N

213

S

S

1. s-BuLi, TMEDA,

Et2O, _78 °C, 3 h

2. pTolSSpTol, 18 h


mmol, 1.3 eq.), TMEDA (227 mg, 1.95 mmol, 1.3 eq.) and thioamide 210 (257 mg,

1.50 mmol, 1.0 eq.) in THF (6 mL) at −78 °C for 3 h and a solution of p-tolyldisulfide

(739 mg, 3.0 mmol, 2.0 eq.) in THF (1 mL) gave the crude product which contained

none of the desired product by 1H NMR spectroscopy. Purification by flash column

chromatography on silica with 4:1 petrol-Et2O as eluent gave starting thioamide 210

(201 mg, 78%) as pale yellow needles.



220

2,2-Dimethyl-1-(2-(p-tolylsulfinyl)azetidin-1-yl)propane-1-thione 192

N

S

S

O

H

192



eq.) and TMEDA (358 μL, 2.40 mmol, 2.4 eq.) in THF (6 mL) at −78 °C under Ar. The

resulting solution was stirred at −78 °C for 30 min. Then, methyl p-toluenesulfinate

121 (340 mg, 2.0 mmol, 2.0 eq.) and the solution was allowed to warm to rt over 2 h

and stirred at rt for 16h. Saturated NH4Cl(aq) (10 mL) was added and the two layers

were separated. The aqueous layer was extracted with Et2O (3 × 10 mL). The


give the crude product which contained a 91:9 mixture of diastereoisomers by 1H NMR.


eluent gave sulfoxide 192 (27 mg, 9%) as a colourless oil, RF (7:3 petrol-EtOAc) 0.2; IR

(film) 2987, 2954, 1502, 1480, 1424, 1395, 1240, 1140, 1025, 728 cm−1

; 1

H NMR (400

MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 1H, m-C6H4Me), 7.32 (d, J = 8.0 Hz, 1H, o-

C6H4Me), 5.55 (dd, J = 9.0, 4.5 Hz, 1H, NCH), 4.50 (dt, J = 9.0, 7.0 Hz, 1H,

NCHACHB), 4.34 (dt, J = 9.0, 4.5 Hz, 1H, NCHACHB), 2.83 (ddt, J = 12.0, 9.0, 4.5 Hz,

1H, CHACHB), 2.41 (s, 3H, Me), 2.06 (dtd, J = 12.0, 9.0, 7.0 Hz, 1H, CHACHB), 1.39 (s,

9H, CMe3); 13

C NMR (100.6 MHz, CDCl3) δ 213.5 (C=S), 141.3 (ipso-Ar), 137.3 (ipso-

Ar), 129.9 (Ar), 123.9 (Ar), 86.0 (NCH), 56.5 (NCH2), 43.8 (CMe3), 29.7 (CMe3), 21.3

(Me) 17.3 (CH2); MS (ESI) m/z 318 [(M + Na)+, 100], 296 [(M + H)

+, 50]; HRMS m/z

calcd for C15H21NOS2 (M + Na)+ 318.0962, found 318.0960 (−0.5 ppm error) and

recovered N-thiopivaloyl azetidine 101 (113 mg, 72%). Diagnostic signal for other

diastereoisomer: 1H NMR (400 MHz, CDCl3) δ 5.72 (dd, J = 9.0, 4.0 Hz, 1H, NCH).



221

Attempted synthesis of 2,2-dimethyl-1-((S)-2-((S)-p-tolylsulfinyl)azetidin-1-

yl)propane-1-thione (S,SS)-192 and 2,2-dimethyl-1-((R)-2-((S)-p-

tolylsulfinyl)azetidin-1-yl)propane-1-thione (R,SS)-192

N

S

S

O

H

N

S

S

O

H

(R,SS)-192(S,SS)-192


Et2O, _78 °C, 30 min

2.N

S

101 SO

O

(SS)-97

Using general procedure L, s-BuLi (0.92 mL of a 1.3M solution in hexanes, 1.20 mmol,

1.2 eq.), N-thiopivaloyl azetidine 101 (158 mg, 1.00 mmol, 1.0 eq.) and (−)-sparteine

(0.28 mL, 1.20 mmol, 1.2 eq.) in Et2O (7 mL) and a solution of Andersen’s sulfinate

(441 mg, 1.50 mmol, 1.5 eq.) gave the crude product. The 1H NMR spectrum of the

crude product showed no evidence of sulfoxides (S,SS)-192 and (R,SS)-192. Purification

by flash column chromatography on silica with 9:1-8:2 petrol-Et2O gave recovered N-

thiopivaloyl azetidine 101 (134 mg, 85%)


Chloromethyl p-tolylsulfide 215166

215

Cl S

N-Chlorosuccinimide (3.67 g, 27.5 mmol, 1.1 eq., recrystallised from glacial AcOH)

was added to a stirred solution of methyl p-tolylsulfide (3.45 g, 25.0 mmol, 1.0 eq.) in

CHCl3 (25 mL) at 0 °C. The resulting solution was allowed to warm to rt over 5 min

and then stirred at rt for 18 h. Then, 4% NaI(aq) (50 mL) was added and the two layers

were separated. The organic layer was washed with 10% Na2S2O3(aq) (50 mL), dried

(Na2SO4) and evaporated under reduced pressure to give a 90:10 mixture (by 1H NMR

spectroscopy) of chlorosulfide 215 and methyl p-tolylsulfide (4.12 g, 90% yield of

chlorosulfide 215) as a pale yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.0


222

Hz, 2 H, o-C6H4Me), 7.18 (d, J = 8.0 Hz, 2 H, m-C6H4Me), 4.92 (s, 2H, CH2), 2.36 (s,

3H, Me). Attempted purification by flash column chromatography on silica gel and by

fractional distillation led to product decomposition.


N-(4-Methoxyphenyl)benzamide 214165

214

OMe

NH

O

Ph

Benzoyl chloride (2.92 mL, 25.1 mmol, 1.1 eq.) was added dropwise to a stirred

suspension of p-anisidine (2.80 g, 22.8 mmol, 1.0 eq.) and NaHCO3 (5.76 g, 68.4 mmol,

3.0 eq.) in CH2Cl2 (120 mL) at 0 °C under Ar. The resulting suspension was stirred at 0

°C for 1 h. Then, water (100 mL) was added and the two layers were separated. The

aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The combined organic layers

were washed with brine (100 mL), dried (Na2SO4) and evaporated under reduced

pressure to give the crude product. Purification by flash column chromatography on

silica with 7:3 petrol-EtOAc as eluent gave benzamide 214 (4.28 g, 83%) as purple

crystals, mp 146-149 °C, (lit.,225

153-156 °C); RF (7:3 petrol-EtOAc) 0.3; 1H NMR (400

MHz, CDCl3) δ 7.87 (d, J = 7.5 Hz, 2H, o-Ph), 7.73 (br s, 1H, NH), 7.57-7.50 (m, 5H,

Ar), 6.92 (d, J = 9.0 Hz, 2H, Ar), 3.83 (s, 3H, OMe); 13


165.6 (C=O), 156.6 (ipso-C6H4OMe), 135.0 (ipso-Ar), 131.7 (Ar), 131.0 (ipso-Ar),

128.8 (Ar), 128.4 (Ar), 127.1 (Ar), 122.2 (Ar), 114.3 (Ar), 55.6 (OMe). Spectroscopic

data consistent with those reported in the literature.226



223

N-(4-Methoxyphenyl)-N-p-tolylsulfanylmethyl benzamide 216164

216

OMe

N

O

Ph S

A 90:10 mixture (by 1H NMR spectroscopy) of chlorosulfide 215 and methyl p-

tolylsulfide (1.80 g, 9.38 mmol of chlorosulfide 215, 2.5 eq.) was added to a stirred

solution of tetraethylammonium iodide (430 mg, 1.88 mmol, 0.5 eq.) and benzamide

214 (850 mg, 3.75 mmol, 1.0 eq.) in CH2Cl2 (7.5 mL) at rt. The resulting solution was

cooled to 0 °C and 50% NaOH(aq) (17.5 mL) was added. The resulting solution was

heated at 50 °C for 18 h. Then, the solution was allowed to cool to rt and poured into

saturated NH4Cl(aq) (50 mL). The two layers were separated and the aqueous layer was

extracted with Et2O (3 × 30 mL). The combined organic layers were dried (Na2SO4)

and evaporated under reduced pressure to give the crude product. Purification by flash

column chromatography on silica with 65:35 petrol-EtOAc as eluent gave benzamide

216 (922 mg, 67%) as a colourless oil, RF (65:35 petrol-EtOAc) 0.4; IR (film) 2955,

1649 (C=O), 1510, 1493, 1446, 1372, 1250, 1144, 1039, 729 cm−1

; 1

H NMR (400 MHz,

CDCl3) δ 7.27-7.21 (m, 5H, Ar), 7.16 (t, J = 7.5 Hz, 2H, Ar), 7.04 (d, J = 8.0 Hz, 2H,

Ar), 6.93 (d, J = 8.0 Hz, 2H, Ar), 6.69 (d, J = 8.0 Hz, 2H, Ar), 5.30 (s, 2H, NCH2), 3.73

(s, 3H, OMe), 3.00 (s, 3H, Me); 13

C NMR (100.6 MHz, CDCl3) δ 170.4 (C=O), 158.3

(ipso-C6H4OMe), 137.1 (ipso-Ar), 135.3 (ipso-Ar), 135.1 (ipso-Ar), 132.2 (Ar), 130.9

(ipso-Ar), 130.4 (Ar), 129.7 (Ar), 129.4 (Ar), 128.6 (Ar), 127.6 (Ar), 114.2 (Ar), 55.9

(NCH2), 55.3 (OMe), 21.0 (Me); MS (ESI) m/z 386 [(M + Na)+, 100], 364 [(M + H)

+,

20], 240 (50); HRMS m/z calcd for C22H21NO2S (M + Na)+ 386.1185, found 386.1175

(+2.6 ppm error).



224

N-(4-Methoxyphenyl)-N-p-tolylsulfinylmethyl benzamide 193

193

OMe

N

O

Ph S

O

Using general procedure G, m-CPBA (68 mg of ~77% purity, 0.31 mmol, 1.1 eq.) and

sulfanyl benzamide 216 (100 mg, 0.28 mmol, 1.0 eq.) in CH2Cl2 (1.8 mL) gave the

crude product as a viscous foam. Purification by flash column chromatography on

silica with 7:3 EtOAc-petrol as eluent gave sulfoxide 193 (88 mg, 84%) as an orange

oil, RF (7:3 EtOAc-petrol) 0.3; IR (film) 3056, 2932, 2837, 1650 (C=O), 1513, 1446,

1359, 1294, 1178, 1084, 1045 cm−1

; 1

H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.0 Hz,

2H, m-C6H4Me), 7.32 (d, J = 7.5, 2H Hz, o-Ph), 7.30 (d, J = 8.0 Hz, 2H, o-C6H4Me),

7.26 (br t, J = 7.5 Hz, 1H, p-Ph), 7.16 (t, J = 7.5 Hz, 2H, m-Ph), 7.10 (d, J = 8.5 Hz, 2H,

Ar), 6.69 (d, J = 8.5 Hz, 2H, Ar), 5.20 (d, J = 12.5 Hz, 1H, NCH2), 4.49 (d, J = 12.5 Hz,

1H, NCH2), 3.70 (s, 3H, OMe), 2.38 (s, 3H, Me); 13


170.7 (C=O), 158.3 (ipso-C6H4OMe), 141.7 (ipso-Ar), 138.8 (ipso-Ar), 135.9 (ipso-Ar),

134.3 (ipso-Ar), 130.2 (Ar), 129.9 (Ar), 128.9 (Ar), 128.8 (Ar), 127.8 (Ar), 124.3 (Ar),

114.3 (Ar), 76.9 (NCH2), 55.3 (OMe), 21.4 (Me); MS (ESI) m/z 402 [(M + Na)+, 100],

240 [(M – S(O)C6H4Me)+, 50]; HRMS m/z calcd for C22H21NO3S (M + Na)

+ 402.1134,

found 402.1124 (+2.5 ppm error).


N-(4-Methoxyphenyl)thiobenzamide 217

217

OMe

NH

S

Ph

Phosphorous(V) sulfide (918 mg, 4.13 mmol, 1.25 eq.) was added to a stirred solution

benzamide 214 (750 mg, 3.30 mmol, 1.0 eq.) in pyridine (15 mL) at rt under Ar. The


225

resulting solution was heated at 75 °C for 6 h. The solution was allowed to cool to rt and

then poured into 1 M HCl(aq) (50 mL). 1 M HCl(aq) was added until pH 3 was obtained.

The resulting solution was stirred for 2 h and then extracted with CH2Cl2 (3 × 50 ml).

Combined organic extracts were washed with 1 M HCl(aq) (50 mL), water (50 mL) and


product. Purification by flash column chromatography on silica with 4:1 petrol-EtOAc

as eluent gave thiobenzamide 217 (320 mg, 40%) as a pale yellow oil, RF (4:1 petrol-

EtOAc) 0.2; 1H NMR (400 MHz, CDCl3) δ 8.94 (br s, 1H, NH), 7.88 (dd, J = 7.0, 1.5

Hz, 2H, o-Ph), 7.67 (d, J = 8.5 Hz, 2H, Ar), 7.52 (dddd, J = 7.0, 7.0, 1.5, 1.5 Hz, 1H, p-

Ph), 7.45 (dd, J = 7.0, 7.0 1.5 Hz, 2H, m-Ph), 6.98 (d, J = 8.5 Hz, 2H, Ar), 3.86 (s, 3H,

OMe); MS (ESI) m/z 266 [(M + Na)+, 20], 244 [(M + H)

+, 100], 159 (30), 141 (30), 125

(30); HRMS m/z calcd for C14H13NOS (M + H)+ 244.0791, found 244.0786 (+2.0 ppm

error).


N-(4-Methoxyphenyl)-N-p-tolylsulfanylmethylthiobenzamide 218164

218

OMe

N

S

Ph S


tolylsulfide (481 mg, 2.48 mmol of chlorosulfide 215, 2.5 eq.) was added to a stirred

solution of tetraethylammonium iodide (112 mg, 0.50 mmol, 0.5 eq.) and

thiobenzamide 217 (240 mg, 0.99 mmol, 1.0 eq.) in CH2Cl2 (4.5 mL) at rt. The

resulting solution was cooled to 0 °C and then 50% NaOH(aq) (2.5 mL) was added. The

resulting solution was heated at 50 °C for 18 h. Then, the solution was allowed to cool

to rt and poured into saturated NH4Cl(aq) (10 mL). The two layers were separated and

the aqueous layer was extracted with Et2O (3 × 15 mL). The combined organic layers



gave sulfanyl thiobenzamide 218 (204 mg, 54%) as a colourless oil, RF (9:1 petrol-


226

EtOAc) 0.3; 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.0 Hz, 2H, Ar), 7.24-7.14 (m,

5H, Ar), 6.93 (br s, 2H, Ar), 6.70 (d, J = 8.5 Hz, 2H, Ar), 6.60 (d, J = 8.5 Hz, 2H, Ar),

4.64 (s, 2H, NCH2), 3.74 (s, 3H, OMe), 2.35 (s, 3H, Me); MS (ESI) m/z 402 [(M +

Na)+, 100], 380 [(M + H)

+, 50]; HRMS m/z calcd for C22H21NOS2 (M + Na)

+ 402.0962,

found 402.0968 (+2.5 ppm error).


N-(4-Methoxyphenyl)-N-p-tolylsulfinylmethyl thiobenzamide 194

194

OMe

N

S

Ph S

O

Using general procedure G, m-CPBA (141 mg of ~70% purity, 0.57 mmol, 1.1 eq.) and

sulfanyl thiobenzamide 218 (200 mg, 0.52 mmol, 1.0 eq.) in CH2Cl2 (3.5 mL) gave the

crude product as a viscous foam. Purification by flash column chromatography on

silica with 7:3 EtOAc-petrol as eluent gave sulfoxide 194 (158 mg, 77%) as a viscous

orange foam, RF (7:3 EtOAc-petrol) 0.2; IR (CHCl3) 2833, 1613 (C=S), 1502, 1443,

1242, 1178, 1047, 956, 832 cm−1

; 1

H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz,

2H, m-C6H4Me), 7.34-7.19 (m, 7H, Ar), 6.69 (d, J = 8.0 Hz, 2H, Ar), 6.51 (d, J = 8.5

Hz, 2H, Ar), 4.57 (d, J = 13.0 Hz, 1H, NCHAHB), 4.45 (d, J = 13.0 Hz, 1H, NCHAHB),

3.74 (s, 3H, OMe), 2.40 (s, 3H, Me); 13

C NMR (100.6 MHz, CDCl3) rotamers δ 208.1

(C=S), 156.1 (ipso-C6H4OMe), 141.7 (ipso-Ar), 140.1 (ipso-Ar), 135.1 (br, ipso-Ar),

130.0 (ipso-Ar), 129.6 (Ar), 128.5 (Ar), 128.0 (Ar), 127.5 (Ar), 124.7 (Ar), 122.7 (Ar),

113.9 (Ar), 60.4 (NCH2), 55.8 (OMe), 55.3 (OMe), 21.4 (Me), 14.6 (Me); MS (ESI) m/z

396 [(M + H)+, 100]; HRMS m/z calcd for C22H21NO2S2 (M + H)

+ 396.1086, found

396.1092 (−0.4 ppm error).



227

tert-Butyl N-(4-methoxyphenyl)carbamate 219227

219

OMe

NHBoc

A solution of di-tert-butyl dicarbonate (4.80 g, 22.0 mmol, 1.0 eq.) in THF (15 mL) was

added to a stirred solution of p-Anisidine (3.69, 30.0 mmol, 1.3 eq.) in THF (15 mL) at

rt under Ar. The resulting solution was stirred at rt for 18 h. Then, CH2Cl2 (50 mL) and

water (50 mL) were added and the two layers were separated. The aqueous layer was

extracted with CH2Cl2 (2 × 50 mL). The combined organic layers were washed with


product as colourless oil. Purification by flash column chromatography on silica with

7:3 EtOAc-petrol as eluent gave N-Boc p-anisidine 219 (3.98 g, 81%) as a white solid,

mp 84-87 °C, (lit.,227

92-94 °C); RF (7:3 petrol-EtOAc) 0.5; 1H NMR (400 MHz,

CDCl3) δ 7.27 (br d, J = 8.0 Hz, 2H, Ar), 6.84 (d, J = 8.0 Hz, 2H, Ar), 6.34 (br s, 1H,

NH), 3.79 (s, 3H, OMe), 1.57 (s, 9H, CMe3), Spectroscopic data consistent with those



tert-Butyl N-(4-methoxyphenyl) N-methylcarbamate 221228

221

OMe

NBoc

A solution of N-Boc p-anisidine 219 (256 mg, 1.15 mmol, 1.0 eq.) in THF (3 mL) was

added to a stirred solution of NaH (51 mg of 60% wt in mineral oil, 1.27 mmol, 1.1 eq.)

and methyl iodide (179 mg, 1.27 mmol, 1.1 eq.) in THF (2 mL) at rt under Ar. The

resulting solution was stirred at rt for 18 h. Then, the reaction was cooled to 0 °C and

water (7 mL) and Et2O (7 mL) were added. The two layers were separated and the

aqueous layer was extracted with E2O (2 × 10 mL). The combined organic layers were


228

dried (MgSO4) and evaporated under reduced pressure to give N-Boc N-methyl p-

ansidine 221 (265 mg, 98%) as colourless oil which was sufficiently pure (by 1H NMR

spectroscopy) for subsequent use, 1H NMR (400 MHz, CDCl3) δ 7.27 (br d, J = 8.0 Hz,

2H, Ar), 6.85 (d, J = 8.0 Hz, 2H, Ar), 3.80 (s, 3H, OMe), 3.22 (s, 3H, NMe), 1.44 (s,

9H, CMe3); 13

C NMR (100.6 MHz, CDCl3) δ 159.9 (ipso-C6H4OMe), 155.2 (C=O),

135.2 (ipso-Ar), 122.6 (Ar), 117.5 (Ar), 79.8 (CMe3), 57.6 (OMe), 28.7 (CMe3), 28.3

(NMe). Spectroscopic data consistent with those reported in the literature.229


Attempted synthesis of tert-Butyl N-(4-Methoxyphenyl)-N-p-tolylsulfanylmethyl

carbamate 220 (via alkylation)

Et4NI, 50% NaOH(aq),

CH2Cl2, 50 °C, 18h

NBoc

OMe

SSCl

215

NHBoc

OMe

219 220


tolylsulfide (430 mg, 2.25 mmol of chlorosulfide 215, 3.0 eq.) was added to a stirred

solution of tetraethylammonium iodide (86 mg, 0.38 mmol, 0.5 eq.) and N-Boc p-

anisidine 219 (167 mg, 0.75 mmol, 1.0 eq.) in CH2Cl2 (3.5 mL) at rt. The resulting

solution was cooled to 0 °C and then 50% NaOH(aq) (1.5 mL) was added. The resulting

solution was heated at 50 °C for 18 h. Then, the solution was allowed to cool to rt and

poured into saturated NH4Cl(aq) (10 mL). The two layers were separated and the




gave recovered N-Boc p-anisidine 219 (165 mg, 100%) as a white solid.



229

NBoc

OMe

S

SCl

215

NHBoc

OMe

219 220

1. NaH, 0 °C,15 min

2. 215, rt, 18 h

A solution of N-Boc p-anisidine 219 (256 mg, 1.15 mmol, 1.0 eq.) in THF (3 mL) was

added to a stirred solution of NaH (51 mg of 60% wt in mineral oil, 1.27 mmol, 1.1 eq.)

in THF (2 mL) at rt under Ar. The resulting solution was stirred at rt for 15 min. Then, a

90:10 mixture (by 1H NMR spectroscopy) of chlorosulfide 215 and methyl p-

tolylsulfide (287 mg, 1.50 mmol of chlorosulfide 215, 2.0 eq.) was added. The resulting

solution was stirred for 18 h at rt. Then, water (7 mL) and Et2O (7 mL) were added.

The two layers were separated and the aqueous layer was extracted with E2O (2 × 10


pressure to give the crude product. The 1H NMR spectrum of the crude product showed

no formation of sulfanyl anisidine 220, therefore no further purification was attempted.


Attempted synthesis of tert-Butyl N-(4-Methoxyphenyl)-N-p-tolylsulfanylmethyl

carbamate 220 (via lithiation-trapping)

NBoc

OMe

SNBoc

OMe

221

Me1. s-BuLi, TMEDA,

THF, _78 °C, 2 h

220

2. pTolSSpTol, 18 h


dropwise to a stirred solution of the N-Boc N-methyl p-anisidine 221 (300 mg, 1.26

mmol, 1.0 eq.) and TMEDA (288 mg, 2.52 mmol, 2.0 eq.) in THF (5.0 mL) at −78 °C

under Ar. The resulting solution was stirred at −78 °C for 2 h. Then, a solution of p-

tolyldisulfide (610 mg, 2.52 mmol, 2.0 eq.) in THF (1.0 mL) was added dropwise. The


230

solution was allowed to warm slowly to rt over 2 h and stirred at rt for 16 h. Saturated

NH4Cl(aq) (10 mL) was added and the two layers were separated. The aqueous layer was



column chromatography on silica with 7:3 petrol-Et2O as eluent gave recovered N-Boc

N-methyl p-anisidine 221 (155 mg, 52%) as a colourless oil.


N-tert-Butoxycarbonyl-N,N-dimethylamine 222167

222

Nt-BuO

O

A solution of di-tert-butyl dicarbonate (5.24 g, 24.0 mmol, 1.2 eq.) in 1:1 THF-water

(100 mL) was added to a stirred solution of dimethylamine (2.28 mL of a 40% wt

solution in water, 20.0 mmol, 1.0 eq.) and NaHCO3 (2.00 g, 24.0 mmol, 1.2 eq.) in 1:1

THF-water (100 mL) at rt under Ar. The resulting solution was stirred at rt for 18 h.

Then, Et2O (100 mL) was added and the two layers were separated. The aqueous layer

was extracted with Et2O (2 × 50 mL). The combined organic layers were dried

(Na2SO4) and evaporated under reduced pressure to give the crude product as colourless

oil. Purification by Kügelrohr distillation gave N-Boc dimethylamine 222 (2.09 g, 72%)


75-80 °C/16-17 mmHg); 1H NMR

(400 MHz, CDCl3) δ 2.86 (s, 6H, NMe2), 1.44 (s, 9H, CMe3); 13

C NMR (100.6 MHz,

CDCl3) δ 156.2 (C=O), 79.8 (CMe3), 36.5 (NMe2), 28.4 (CMe3). Spectroscopic data



N-Methyl N-p-tolylsulfinylmethyl carbamic acid tert-butyl ester 196

196

Nt -BuO

O

S

O


231


1.3 eq.), TMEDA (151 mg, 0.19 mL, 1.30 mmol, 1.3 eq.) and N-Boc dimethylamine

222 (145 mg, 1.00 mmol, 1.0 eq.) in Et2O (2 mL) at −78 °C for 2 h and methyl p-

toluenesulfinate 121 (340 mg, 2.00 mmol, 2.0 eq.) gave the crude product. Purification

by flash column chromatography on silica with 98:2: CH2Cl2-acetone with 1% Et3N as

eluent gave sulfoxide 196 (202 mg, 71%) as a colourless oil, RF (98:2 CH2Cl2-acetone

with 1% Et3N) 0.3; IR (Film) 2977, 2930, 1712 (C=O), 1493, 1454, 1370, 1288, 1163,

1045, 871 cm−1

; 1

H NMR (400 MHz, CDCl3) (50:50 mixture of rotamers) δ 7.55 (d, J =

8.0 Hz, 1H, m-C6H4Me), 7.51 (d, J = 8.0 Hz, 1H, m-C6H4Me), 7.35 (d, J = 8.0 Hz, 1H,

o-C6H4Me), 7.33 (d, J = 8.0 Hz, 1H, o-C6H4Me), 4.58 (d, J = 13.0 Hz, 0.5H, NCHAHB),

4.37 (d, J = 13.0 Hz, 0.5H, NCHAHB), 4.30 (d, J = 13.0 Hz, 0.5H, NCHAHB), 4.11 (d, J

= 13.0 Hz, 0.5H, NCHAHB), 3.06 (s, 1.5H, NMe), 2.94 (s, 1.5H, NMe), 2.42 (s, 1.5H,

C6H4Me), 2.41 (s, 1.5H, C6H4Me), 1.43 (s, 4.5H, CMe3), 1.39 (s, 4.5H, CMe3); 13

C

NMR (100.6 MHz, CDCl3) rotamers δ 155.2 (C=O), 154.2 (C=O), 142.0 (ipso-

C6H4S(O)), 141.7 (ipso-C6H4S(O)), 138.7 (ipso-C6H4Me), 138.4 (ipso-C6H4Me), 130.1

(Ar), 129.9 (Ar), 124.3 (Ar), 124.2 (Ar), 81.2 (CMe3), 81.0 (CMe3), 74.6 (NCH2), 74.5

(NCH2), 37.0 (NMe), 36.3 (NMe), 28.2 (CMe3), 28.0 (CMe3), 21.4 (br, C6H4Me); MS

(ESI) m/z 306 [(M + Na)+, 100]; HRMS m/z calcd for C14H21NO3S (M + Na)

+ 306.1134,

found 306.1135 (−0.3 ppm error).


tert-Butyl 4-hydroxypiperidine-1-carboxylate 302

N

Boc

OH

302

NaBH4 (200 mg, 7.5 mmol, 1.5 eq.) was added to a stirred solution of N-Boc piperidin-

4-one (1.00 g, 5.0 mmol, 1.0 eq.) in EtOH (5 mL) at 0 °C under Ar. The resulting

solution was allowed to warm to rt and stirred at rt for 4 h. Then, the mixture was

cooled to 0 °C and saturated NH4Cl(aq) (20 mL) was added dropwise. The solvent was

evaporated under reduced pressure and EtOAc (15 mL) was added. The two layers

were separated and the aqueous layer was extracted with EtOAc (2 × 15 mL). The


232


give the crude product. Purification by flash column chromatography on silica with 9:1

CH2Cl2-acetone as eluent gave N-Boc 4-hydoxy piperidine 302 (984 mg, 98%) as a

white solid, mp 66-68 °C (lit.,230

64.6-66.5 °C); RF (9:1 CH2Cl2-Acetone) 0.2; 1H NMR

(400 MHz, CDCl3) δ 3.82-3.72 (m, 3H, NCHAHB + CHOH ), 2.97 (ddd, J = 13.0, 10.0,

3.0 Hz, 2H, NCHAHB), 2.67 (br s, 1H, OH), 1.83-1.78 (m, 2H, NCH2CHAHB), 1.46-1.37

(m, 2H, NCH2CHAHB), 1.41 (s, 9H, CMe3); 13

C NMR (100.6 MHz, CDCl3) δ 154.7

(C=O), 79.5 (CMe3), 67.4 (CHOH), 41.3 (br, NCH2), 34.0 (NCH2CH2), 28.3 (CMe3).


tert-Butyl 4-chloropiperidine-1-carboxylate 223

N

Boc

223

Cl

A solution of hexachloroethane (7.05 g, 29.8 mmol, 2.0 eq.) in CH2Cl2 (25 mL) was

added to a stirred solution of N-Boc 4-hydroxy piperidine 302 (3.00 g, 14.9 mmol, 1.0

eq.) and PPh3 (7.82 g, 29.8 mmol, 2.0 eq.) in CH2Cl2 (75 mL) at rt under Ar. The

resulting solution was stirred at rt for 16 h. The solvent was evaporated under reduced


silica with 4:1 petrol-Et2O as eluent gave N-Boc 4-chloro piperidine 223 (2.13 g, 67%)

as a colourless oil, RF (4:1 petrol-Et2O) 0.3; IR (film) 2974, 2932, 1696 (C=O), 1477,

1420, 1365, 1277, 1169, 1112, 1002 cm-1

; 1

H NMR (400 MHz, CDCl3) δ 4.20 (tt, J =

7.5, 3.5 Hz, 1H, CHCl), 3.69 (ddd, J = 13.0, 7.0, 3.5 Hz, 2H, NCHAHB), 3.29 (ddd, J =

13.0, 7.5 Hz, 2H, NCHAHB), 2.01 (ddt, J = 13.5, 7.0, 3.5 Hz, 2H, NCH2CHAHB), 1.78

(dtd, J = 13.5, 7.5, 3.5 Hz, 2H, NCH2CHAHB), 1.45 (s, 9H, CMe3); 13

C NMR (100.6

MHz, CDCl3) δ 154.6 (C=O), 79.7 (CMe3), 56.9 (CHCl), 41.2 (br, NCH2), 34.8

(NCH2CH2), 28.3 (CMe3); MS (ESI) m/z 244 [(37

M + Na)+, 10], 242 [(

35M + Na)

+, 30],

166 (30), 164 (100); HRMS m/z calcd for C10H1835

ClNO2 (M + Na)+ 242.0918, found

242.0911 (+3.1 ppm error).


233

tert-Butyl (1R,5R)-(p-tolylsulfinyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate syn-

(R,R,Ss)-225 and tert-Butyl (1S,5S)-(p-tolylsulfinyl)-2-azabicyclo[3.1.0]hexane-2-

carboxylate anti-(S,S,Ss)-225


syn-(R,R,SS)-225

N

Boc

S

O

anti-(S,S,SS)-225

N

Boc

S

O

Using general procedure H, s-BuLi (1.70 mL of a 1.3 M solution in hexanes, 2.20

mmol, 2.2 eq.), N-Boc 4-chloro piperidine 223 (219 mg, 1.00 mmol, 1.0 eq.) and

TMEDA (256 mg, 2.20 mmol, 2.2 eq.) in Et2O (6 mL) at −78 °C for 1 h and a solution

of Andersen’s sulfinate (SS)-97 (647 mg, 2.20 mmol, 2.2 eq.) in THF (2 mL) gave the


EtOAc + 1% Et3N as eluent gave sulfoxide syn-(R,R,SS)-225 (129 mg, 38%, 58:42 er by

CSP-HPLC) as a white solid, mp 163-166 °C; RF (3:2 petrol-EtOAc) 0.3; IR (CHCl3)

2975, 2931, 1703 (C=O), 1492, 1454, 1393, 1368, 1257, 1168, 1083, 810 cm-1

; 1H NMR

(400 MHz, CDCl3) δ 7.50-7.48 (m, 2H, m-C6H4Me), 7.28 (d, J = 8.0 Hz, 2H, o-

C6H4Me), 3.47 (br s, 1H, NCHAHB), 2.84 (br s, 1H, NCHAHB), 2.41 (s, 3H, Me), 2.28

(br s, 1H, CH), 1.93-1.90 (m, 1H, CH), 1.77-1.74 (m, 2H, CH), 1.52 (br s, 9H, CMe3),

1.16-1.13 (m, 1H, CH); 13

C NMR (100.6 MHz, CDCl3) (rotamers) δ 155.0 (br, C=O),

141.9 (ipso-Ar), 141.6 (ipso-Ar), 141.1 (ipso-Ar), 139.5 (ipso-Ar), 129.7 (br, Ar), 125.5

(Ar), 124.8 (Ar), 81.2 (br, CMe3), 61.2 (NCS(O)Ar), 61.1 (NCS(O)Ar), 52.3 (br,

NCH2), 28.5 (CMe3), 26.1 (br, CH2), 23.7 (CH2), 22.3 (CH2), 21.6 (Me), 11.9 (CH),

11.7 (CH); MS (ESI) m/z 344 [(M + Na)+, 30], 322 [(M + H)

+, 100]; HRMS m/z calcd

for C17H23NO3S (M + Na)+ 344.1291, found 344.1286 (+1.5 ppm error); CSP-HPLC:

Chiralcel AD (90:10 Hexane-i-PrOH, 1.0 mL min-1

) syn-(S,S,RS)-225 10.1 min, syn-

(R,R,SS)-225 11.5 min and sulfoxide anti-(S,S,SS)-225 (152 mg, 45%, 70:30 er by CSP-

HPLC) as a colourless oil, RF (3:2 petrol-EtOAc) 0.2; IR (film) 2977, 2932, 1696

(C=O), 1477, 1384, 1335, 1257, 1168, 1083, 1048, 810 cm-1

; 1

H NMR (400 MHz,

CDCl3) δ 7.48 (d, J = 8.0 Hz, 2H, m-C6H4Me), 7.26 (d, J = 8.0 Hz, 2H, o-C6H4Me),

3.79-3.72 (m, 1H, NCHAHB), 3.61 (br s, 1H, NCHAHB), 2.37 (s, 3H, Me), 2.27-2.18 (m,

1H, CH), 2.05 (dtd, J = 8.0, 7.0, 1.5 Hz, 1H, NCCH), 1.83-1.75 (m, 1H, CH), 1.49 (s,

9H, CMe3), 1.09 (t, J = 7.0 Hz, 1H, H), 1.05-1.01 (br m, 1H, CH); 13

C NMR (100.6


234

MHz, CDCl3) δ 155.5 (C=O), 141.4 (ipso-Ar), 138.0 (ipso-Ar), 129.5 (Ar), 124.8 (Ar),

80.9 (CMe3), 69.9 (br, NCS(O)Ar), 52.5 (br, NCH2), 29.9 (br, CH2), 28.4 (CMe3), 26.8

(CH2), 24.3 (br, CH), 21.3 (Me); MS (ESI) m/z 344 [(M + Na)+, 40], 322 [(M + H)

+,

100]; HRMS m/z calcd for C17H23NO3S (M + Na)+ 344.1291, found 344.1286 (+1.3

ppm error); CSP-HPLC: Chiralcel AD (90:10 Hexane-iPrOH, 1.0 mL min-1

) anti-

(S,S,Ss)-225 9.0 min, anti-(R,R,Rs)-225 12.3 min.


Using general procedure I, s-BuLi (1.70 mL of a 1.3 M solution in hexanes, 2.20 mmol,

2.2 eq.), N-Boc 4-chloro piperidine 223 (219 mg, 1.00 mmol, 1.0 eq.) and TMEDA (256

mg, 2.20 mmol, 2.2 eq.) in Et2O (6 mL) at −78 °C for 1 h and a solution of Andersen’s



Et3N as eluent gave sulfoxide syn-(R,R,SS)-225 (122 mg, 36%, 80:20 er by CSP-HPLC)

as a white solid, CSP-HPLC: Chiralcel AD (90:10 Hexane-i-PrOH, 1.0 mL min-1

) syn-

(S,S,RS)-225 10.7 min, syn-(R,R,SS)-7 12.3 min and sulfoxide anti-(S,S,SS)-225 (157 mg,

47%, 78:22 er by CSP-HPLC) as a colourless oil, CSP-HPLC: Chiralcel AD (90:10


) anti-(S,S,Ss)-225 9.4 min, syn-(R,R,Rs)-225 13.1 min.


Using general procedure J, s-BuLi (1.70 mL of a 1.3 M solution in hexanes, 2.20 mmol,

2.2 eq.), N-Boc 4-chloro piperidine 223 (219 mg, 1.00 mmol, 1.0 eq.) and TMEDA (256

mg, 2.20 mmol, 2.2 eq.) in Et2O (6 mL) and a solution of Andersen’s sulfinate (Ss)-97

(647 mg, 2.20 mmol, 2.2 eq.) in THF (5 mL) gave the crude product. Purification by

flash column chromatography on silica with 3:2 petrol-EtOAc + 1% Et3N as eluent gave

sulfoxide syn-(R,R,SS)-225 (132 mg, 39%, 89:11 er by CSP-HPLC) as a white solid,

CSP-HPLC: Chiralcel AD (90:10 Hexane-i-PrOH, 1.0 mL min-1

) syn-(S,S,RS)-225 13.2

min, syn-(R,R,SS)-225 15.2 min and sulfoxide anti-(S,S,SS)-225 (146 mg, 44%, 88:12 er

by CSP-HPLC) as a colourless oil, CSP-HPLC: Chiralcel AD (90:10 Hexane-iPrOH,

1.0 mL min-1



2.2 eq.), N-Boc 4-chloro piperidine 223 (219 mg, 1.00 mmol, 1.0 eq.) and (−)-sparteine

(504 mg, 2.20 mmol, 2.2 eq.) in Et2O (6 mL) and a solution of Andersen’s sulfinate


235

(Ss)-97 (647 mg, 2.20 mmol, 2.2 eq.) in THF (5 mL) gave the crude product.


Et3N as eluent gave sulfoxide syn-(R,R,SS)-7 (88 mg, 27%, 96:4 er by CSP-HPLC) as a

white solid, CSP-HPLC: Chiralcel AD (90:10 Hexane-i-PrOH, 1.0 mL min-1

) syn-

(S,S,RS)-7 10.2 min, syn-(R,R,SS)-7 11.6 min and sulfoxide anti-(S,S,SS)-7 (78 mg, 24%,

89:11 er by CSP-HPLC) as a colourless oil, CSP-HPLC: Chiralcel AD (90:10 Hexane-

iPrOH, 1.0 mL min-1



2.2 eq.), N-Boc 4-chloro piperidine 223 (110 mg, 0.50 mmol, 1.0 eq.) and (+)-sparteine

surrogate (213 mg, 1.10 mmol, 2.2 eq.) in Et2O (4 mL) and a solution of Andersen’s



Et3N as eluent gave sulfoxide syn-(R,R,SS)-225 (42 mg, 26%, 99:1 er by CSP-HPLC) as

a white solid, CSP-HPLC: Chiralcel AD (90:10 Hexane-i-PrOH, 1.0 mL min-1

) syn-

(S,S,RS)-225 9.6 min, syn-(R,R,SS)-225 10.9 min and sulfoxide anti-(S,S,SS)-225 (43 mg,

27%, 93:7 er by CSP-HPLC) as a colourless oil, CSP-HPLC: Chiralcel AD (90:10




2.2 eq.), N-Boc 4-chloro piperidine 223 (219 mg, 1.00 mmol, 1.0 eq.) and diamine

(R,R)-42 (683 mg, 2.20 mmol, 2.2 eq.) in Et2O (6 mL) and a solution of Andersen’s




as a white solid, [α]D −43.7 (c 0.65 in CHCl3); CSP-HPLC: Chiralcel AD (90:10

Hexane-i-PrOH, 1.0 mL min-1

) syn-(S,S,RS)-225 9.9 min, syn-(R,R,SS)-225 11.5 min and

sulfoxide anti-(S,S,SS)-225 (80 mg, 25%, 87:13 er by CSP-HPLC) as a colourless oil,

[α]D +64.6 (c 0.9 in CHCl3); CSP-HPLC: Chiralcel AD (90:10 Hexane-iPrOH, 1.0 mL

min-1




(S,S)-42 (683 mg, 2.20 mmol, 2.2 eq.) in Et2O (6 mL) and a solution of Andersen’s


236




as a white solid, [α]D −43.2 (c 0.7 in CHCl3); CSP-HPLC: Chiralcel AD (90:10 Hexane-

i-PrOH, 1.0 mL min-1

) syn-(S,S,RS)-225 12.2 min, syn-(R,R,SS)-225 14.2 min and

sulfoxide anti-(S,S,SS)-225 (174 mg, 54%, 87:13 er by CSP-HPLC) as a colourless oil,

[α]D +86.1 (c 0.7 in CHCl3); CSP-HPLC: Chiralcel AD (90:10 Hexane-iPrOH, 1.0 mL

min-1


tert-Butyl 1-(p-tolylsulfinyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate syn-rac-225

and anti-rac-225

syn-rac-225

N

Boc

S

O

anti-rac-225

N

Boc

S

O


Using General procedure H, s-BuLi (2.11 mL of a 1.3 M solution in hexanes, 2.75


TMEDA (319 mg, 2.75 mmol, 2.2 eq.) in Et2O (8 mL) at −78 °C for 6 h and methyl p-


by flash column chromatography on silica with 3:2 petrol-EtOAc + 1% Et3N as eluent

gave sulfoxide syn-rac-225 (142 mg, 35%) as a white solid, mp 161-163 °C and

sulfoxide anti-rac-225 (144 mg, 36%) as a colourless oil.


Using General procedure H, s-BuLi (2.11 mL of a 1.3 M solution in hexanes, 2.75


TMEDA (319 mg, 2.75 mmol, 2.2 eq.) in Et2O (8 mL) at −78 °C for 1 h and methyl p-



gave sulfoxide syn-rac-225 (138 mg, 35%) as a white solid and sulfoxide anti-rac-225

(141 mg, 35%) as a colourless oil.


237



stirred solution of N-Boc 4-chloro piperidine 223 (275 mg, 1.25 mmol, 1.0 eq.) in THF

(8 mL) at −78 °C under Ar. The resulting solution was stirred at −78 °C for 1 h. Then,

methyl p-toluenesulfinate 121 (468 mg, 2.75 mmol, 2.2 eq.) was added and the resulting

solution was allowed to warm to rt over 2 h and stirred at rt for 16 h. Saturated





sulfoxide syn-rac-225 (132 mg, 33%) as a white solid and sulfoxide anti-rac-225 (129

mg, 36%) as a colourless oil.



stirred solution of N-Boc 4-chloro piperidine 223 (275 mg, 1.25 mmol, 1.0 eq.) in THF

(8 mL) at −30 °C under Ar. The resulting solution was stirred at −30 °C for 5 min.

Then, methyl p-toluenesulfinate 121 (468 mg, 2.75 mmol, 2.2 eq.) was added and the

resulting solution was allowed to warm to rt over 2 h and stirred at rt for 16 h.





gave sulfoxide syn-rac-225 (85 mg, 21%) as a white solid and sulfoxide anti-rac-225



238

tert-Butyl 4-[[(2,4,6-triisopropylbenzene)sulfonyl]oxy]piperidine-1-carboxylate 234

N

Boc

234

OS

O

O

Triisopropylsulfonyl chloride (4.89 g, 16.15 mmol, 1.3 eq.) was added portionwise to a

stirred solution of N-Boc 4-hydroxy piperidine 302 (2.50 g, 12.42 mmol, 1.0 eq.), Et3N

(1.90 mL, 13.66 mmol, 1.1 eq.) and DMAP (14 mg, 0.12 mmol, 0.01 eq.) in CH2Cl2

(30 mL) at 0 °C under Ar. The resulting solution was allowed to warm to rt and stirred

at rt for 3 h. Then, water (20 mL) was added and the two layers were separated. The

organic layer was washed with 1 M HCl(aq) (20 mL), dried (Na2SO4) and evaporated


chromatography on silica with 4:1 petrol-EtOAc as eluent gave N-Boc 4-sulfonyl

piperidine 234 (984 mg, 98%) as a pale yellow solid, mp 71-73 °C; RF (4:1 petrol-

EtOAc) 0.2; 1H NMR (400 MHz, CDCl3) δ 7.19 (s, 2H, Ar), 4.84 (tt, J = 7.5, 4.0 Hz,

1H, CHOSO2Ar), 4.16 (sept, J = 7.0 Hz, 2H, CHMe2), 3.67 (ddd, J = 13.0, 7.0, 4.0 Hz,

2H, NCHAHB), 3.26 (ddd, J = 13.0, 8.0, 4.0 Hz, 2H, NCHAHB), 2.92 (sept, J = 7.0 Hz,

1H, CHMe2), 1.88 (ddt, J = 13.5, 7.0, 4.0, 2H, NCH2CHAHB), 1.76 (dtd, J = 13.5, 7.0,

4.0, 2H, NCH2CHAHB), 1.45 (s, 9H, CMe3) 1.27 (d, J = 7.0 Hz, 12H, CHMe2), 1.27 (d,

J = 7.0 Hz, 6H, CHMe2); 13

C NMR (100.6 MHz, CDCl3) δ 154.7 (C=O), 153.7 (ipso-

Ar), 150.4 (ipso-Ar), 130.8 (ipso-Ar), 123.8 (Ar), 80.0 (CMe3), 76.9 (CHOSO2Ar), 34.3

(CHMe2), 31.7 (br, NCH2), 29.8 (br, NCH2CH2), 29.7 (CHMe2) 28.5 (CMe3), 24.8

(CHMe2), 23.6 (CHMe2).


tert-Butyl 2-azabicyclo[3.1.0]hexane-2-dicarboxylate rac-227

rac-227

N

Boc


239

Using general procedure H, s-BuLi (7.70 mL of a 1.3M solution in hexanes, 10.01

mmol, 2.2 eq.), N-Boc 4-chloro piperidine 223 (1.00 g, 4.55 mmol, 1.0 eq.) and

TMEDA (1.16 g, 10.01 mmol, 2.2 eq.) in Et2O (20.0 mL) at −78 °C for 1 h and MeOH

(2.0 mL) gave the crude product. Purification by flash column chromatography on

silica with 4:1 petrol-Et2O as eluent gave bicycle rac-227 (723 mg, 87%) as a colourless

oil, RF (4:1 petrol-Et2O) 0.3; IR (film) 2974, 2879, 1670 (C=O), 1411, 1365, 1344,

1254, 1171, 1111, 1081 cm-1

; 1

H NMR (400 MHz, CDCl3) δ 3.54 (br s, 1H, NCHAHB),

3.33-3.26 (br m, 1H, NCH), 2.82 (q, J = 9.0 Hz, 1H, NCHAHB), 1.97 (br s, 1H,

NCH2CHAHB), 1.82 (dtd, J = 12.5, 9.0, 3.0 Hz, 1H, NCH2CHAHB), 1.45-1.34 (m, 1H,

NCHCH), 1.37 (s, 9H, CMe3), 0.57 (br s, 1H, NCHCHAHB), 0.42 (td, J = 5.0, 3.0 Hz,

1H, NCHCHAHB); 13

C NMR (100.6 MHz, CDCl3) δ 155.1 (C=O), 79.0 (CMe3), 43.4

(br, NCH2), 35.3 (NCH), 28.3 (CMe3), 25.4 (CH2), 14.8 (NCHCH), 10.7 (CH2); MS

(ESI) m/z 206 [(M + Na)+, 80], 128 (100); HRMS m/z calcd for C10H17NO2 (M + Na)

+

206.1156, found 206.1151 (−2.0 ppm error).

Lab Book Reference: PJR 4/251 + PJR 4/256

[(1S)-1-phenylethyl]isopropylamine 236231

(S)-236

Ph NH

A stirred solution of (S)-α-methylbenzylamine (3.87 mL, 30.0 mmol, 1.0 eq.) in acetone

(300 mL) was heated to 60 °C and stirred at 60°C for 16 h. Then, the solution was

cooled to rt and the solvent was removed under reduced pressure. The residue was

dissolved in MeOH (100 mL) and NaBH4 (1.70 g, 45.0 mmol, 1.5eq.) was added

portionwise at 0°C under Ar. The resulting solution was stirred at rt for 2h. Then, the

solution was cooled to 0 °C and sat. NH4Cl(aq) (40 mL) was added dropwise. The

solvent was evaporated under reduced pressure and the reaction mixture was taken up in

EtOAc (25mL). The two layers were separated and the aqueous layer was extracted

with EtOAc (2 x 25 mL). Combined organic layers were dried (Na2SO4) and

evaporated under reduced pressure to give the crude product. Purification by Kügelrohr

distillation gave amine (S)-236 (4.86 g, 99%) as a colourless oil, bp 84-86 °C at 9 mm

Hg (lit., 104 °C at 20 mm Hg); 1H NMR (400 MHz, CDCl3) δ 7.34-7.20 (m, 5H, Ph ),

3.88 (q, J = 6.5 Hz, 1H, NCHPh), 2.61 (sept., J = 6.0 Hz, 1H, NCHMe2), 1.34 (d, J =


240

6.5 Hz, 3H, NCH(Ph)Me), 1.02 (d, J = 6.0 Hz, 6H, NCHMeAMeB), 0.99 (d, J = 6.0 Hz,

6H, NCHMeAMeB); 13

C NMR (100.6 MHz, CDCl3) δ 145.9 (ipso-Ph), 128.4 (Ph),

126.7 (Ph), 126.4 (Ph), 55.0 (NCHPh), 45.6 (NCHMe2), 24.8 (Me), 24.0 (Me), 22.1

(Me). Spectroscopic data consistent with those reported in the literature.231


tert-Butyl-(1S,5R)-(phenylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

(S,R)-235


(S,R)-235

N

Boc

HN

O

Ph


mmol, 2.2 eq.), N-Boc 4-chloro piperidine 223 (219 mg, 1.00 mmol, 1.0 eq.) and (−)-

sparteine (516 mg, 2.20 mmol, 2.2 eq.) in Et2O (8 mL) and phenylisocyanate (262 mg,

2.20 mmol, 2.2 eq.) gave the crude product. Purification by flash column

chromatography on silica with 98:2 CH2Cl2-Et2O as eluent gave amide (S,R)-235 (283

mg, 94%, 56:44 er by CSP-HPLC) as a pale yellow solid, CSP-HPLC: Chiracel OD

(90:10 Hexane-iPrOH, 1.0 mLmin-1

) (R,S)-235 7.2 min, (S,R)-235 13.6 min. Full

characterisation data is presented later.


Using general procedure H, s-BuLi (1.95 mL of a 1.3M solution in hexanes, 2.53 mmol,

2.2 eq.), N-Boc 4-sulfonyl piperidine 234 (540 mg, 1.15 mmol, 1.0 eq.) and (−)-

sparteine (593 mg, 2.53 mmol, 2.2 eq.) in Et2O (6.5 mL) at −78 °C for 1 h and

phenylisocyanate (301 mg, 2.53 mmol, 2.2 eq.) gave the crude product. Purification by

flash column chromatography on silica with 98:2 CH2Cl2-Et2O as eluent gave amide

(S,R)-234 (291 mg, 84%, 58:42 er by CSP-HPLC) as a pale yellow solid, CSP-HPLC:

Chiracel OD (90:10 Hexane-iPrOH, 1.0 mLmin-1

) (R,S)-234 7.2 min, (S,R)-234 14.1

min.



241

Kinetic Resolution of rac-227


s-BuLi (0.70 mL of a 1.3M solution in hexanes, 0.91 mmol, 0.5 eq.) was added

dropwise to a stirred solution of azabicyco[3.1.0] hexane rac-227 (333 mg, 1.82 mmol,

1.0 eq.) and (−)-sparteine (213 mg, 0.91 mmol, 0.5 eq.) in Et2O (5.5 mL) at −78 °C

under Ar. The resulting solution was stirred at −78 °C for 1 h. Then, phenylisocyanate

(130 mg, 1.09 mmol, 0.6 eq.) was added dropwise. The solution was allowed to warm

slowly to rt over 2 h and stirred at rt for 16 h. Saturated NH4Cl(aq) (10 mL) was added




silica with 98:2 CH2Cl2-Et2O as eluent gave recovered azabicyco[3.1.0] hexane (R,S)-

227 (99 mg, 30%, er not determined) and amide (S,R)-235 (198 mg, 36%, 56:44 er by

CSP-HPLC) as a pale yellow solid, CSP-HPLC: Chiracel OD (90:10 Hexane-iPrOH,

1.0 mLmin-1

) (R,S)-235 7.1 min, (S,R)-235 13.7 min.



n-BuLi (0.23 mL of a 2.5M solution in hexanes, 0.58 mmol, 0.5 eq.) was added

dropwise to a stirred solution of azabicyco[3.1.0] hexane rac-227 (210 mg, 1.15 mmol,

1.0 eq.) and (−)-sparteine (136 mg, 0.58 mmol, 0.5 eq.) in Et2O (5.0 mL) at −78 °C

under Ar. The resulting solution was stirred at −78 °C for 1 h. Then, phenylisocyanate

(69 mg, 0.58 mmol, 0.5 eq.) was added dropwise. The solution was allowed to warm

slowly to rt over 2 h and stirred at rt for 16 h. Saturated NH4Cl(aq) (10 mL) was added




silica with 98:2 CH2Cl2-Et2O as eluent gave recovered azabicyco[3.1.0] hexane (R,S)-

227 (110 mg, 52%, er not determined) and amide (S,R)-235 (146 mg, 42%, 56:44 er by

CSP-HPLC) as a pale yellow solid, CSP-HPLC: Chiracel OD (90:10 Hexane-iPrOH,

1.0 mLmin-1

) (R,S)-235 7.4 min, (S,R)-235 14.8 min..



242




(R,R)-237 (572 mg, 1.65 mmol, 2.2 eq.) in Et2O (5 mL) at −78 °C for 1 h and





) (R,S)-235 7.4 min, (S,R)-235 14.8

min.




1.2 eq.), N-Boc 4-chloro piperidine 223 (219 mg, 1.00 mmol, 1.0 eq.) and (−)-sparteine

(281 mg, 1.20 mmol, 1.2 eq.) in Et2O (8 mL) at −78 °C for 1 h and phenylisocyanate

(143 mg, 1.20 mmol, 1.2 eq.) gave the crude product. Purification by flash column

chromatography on silica with 98:2 CH2Cl2-Et2O as eluent gave amide (S,R)-235 (138

mg, 45%, 56:44 er by CSP-HPLC) as a pale yellow solid, CSP-HPLC: Chiracel OD


) (R,S)-235 7.2 min, (S,R)-235 13.3 min..




1.1 eq.), N-Boc 4-sulfonyl piperidine 234 (540 mg, 1.15 mmol, 1.0 eq.) and (−)-

sparteine (296 mg, 1.26 mmol, 1.1 eq.) in Et2O (6.5 mL) at −78 °C for 1 h and





) (R,S)-235 7.4 min, (S,R)-235 14.5

min.



243


A solution of N-Boc 4-chloro piperidine 223 (219 mg, 1.00 mmol, 1.0 eq.) in Et2O (3.0

mL) was added dropwise over 30 min to a stirred solution of s-BuLi (1.69 mL of a 1.3M

solution in hexanes, 2.20 mmol, 2.2 eq.) and (−)-sparteine (515 mg, 2.20 mmol, 2.2 eq.)

in Et2O (3.5 mL) at −78 °C under Ar. The resulting solution was stirred at −78 °C for 3

h. Then, phenylisocyanate (262 mg, 2.20 mmol, 2.2 eq.) was added dropwise. The





column chromatography on silica with 98:2 CH2Cl2-Et2O as eluent gave amide (S,R)-

235 (205 mg, 68%, 54:46 er by CSP-HPLC) as a pale yellow solid, CSP-HPLC:


) (R,S)-235 7.0 min, (S,R)-235 13.4

min.




mL) was added dropwise to a stirred solution of s-BuLi (1.69 mL of a 1.3M solution in

hexanes, 2.20 mmol, 2.2 eq.) and (−)-sparteine (515 mg, 2.20 mmol, 2.2 eq.) in Et2O

(3.5 mL) at −78 °C under Ar. The resulting solution was stirred at −40 °C for 1 h.

Then, phenylisocyanate (262 mg, 2.20 mmol, 2.2 eq.) was added dropwise. The solution

was allowed to warm slowly to rt over 2 h and stirred at rt for 16 h. Saturated NH4Cl(aq)

(10 mL) was added and the two layers were separated. The aqueous layer was extracted

with Et2O (3 × 10 mL). The combined organic layers were dried (Na2SO4) and


column chromatography on silica with 98:2 CH2Cl2-Et2O as eluent gave amide (S,R)-



) (R,S)-235 7.2 min, (S,R)-235 14.1

min.



244


A solution of N-Boc 4-sulfonyl piperidine 234 (350 mg, 0.75 mmol, 1.0 eq.) in Et2O

(3.0 mL) was added dropwise over 30 min via syringe pump to a stirred solution of s-

BuLi (1.28 mL of a 1.3M solution in hexanes, 1.65 mmol, 2.2 eq.) and (−)-sparteine

(386 mg, 1.65 mmol, 2.2 eq.) in Et2O (3.5 mL) at −78 °C under Ar. The resulting

solution was stirred at −78 °C for 3 h. Then, phenylisocyanate (196 mg, 1.65 mmol, 2.2

eq.) was added dropwise. The solution was allowed to warm slowly to rt over 2 h and

stirred at rt for 16 h. Saturated NH4Cl(aq) (10 mL) was added and the two layers were



crude product. Purification by flash column chromatography on silica with 98:2

CH2Cl2-Et2O as eluent gave amide (S,R)-235 (227 mg, 99%, 56:44 er by CSP-HPLC) as

a pale yellow solid, CSP-HPLC: Chiracel OD (90:10 Hexane-iPrOH, 1.0 mLmin-1

)

(R,S)-235 7.0 min, (S,R)-235 13.5 min.

tert-Butyl (1R,5S)-(phenylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

(R,S)-235

(R,S)-235

N

Boc

HN

O

Ph



mmol, 2.2 eq.), N-Boc 4-chloro piperidine 223 (194 mg, 0.89 mmol, 1.0 eq.) and (+)-

sparteine surrogate 1 (381 mg, 1.96 mmol, 2.2 eq.) in Et2O (5.5 mL) and



(R,S)-235 (212 mg, 79%, 54:46 er by CSP-HPLC) as a pale yellow solid, CSP-HPLC:


) (R,S)-235 7.4 min, (S,R)-235 14.8

min.





245

diamine (S,S)-42 (547 mg, 1.76 mmol, 2.2 eq.) in Et2O (5.0 mL) and phenylisocyanate

(124 mg, 1.04 mmol, 1.3 eq.) gave the crude product. Purification by flash column

chromatography on silica with 98:2 CH2Cl2-Et2O as eluent gave amide (R,S)-235 (178

mg, 74%, 67:33 er by CSP-HPLC) as a pale yellow solid, ); [α]D +45.5 (c 1.1 in

CHCl3); CSP-HPLC: Chiracel OD (90:10 Hexane-iPrOH, 1.0 mLmin-1

) (R,S)-235 7.3

min, (S,R)-235 14.3 min .




(S,S)-42 (274 mg, 0.88 mmol, 1.1 eq.) in Et2O (5.0 mL) at −78 °C for 1 h and





) (R,S)-235 7.3 min, (S,R)-235 14.3

min.




mL) was added dropwise to a stirred solution of s-BuLi (1.69 mL of a 1.3M solution in

hexanes, 2.20 mmol, 2.2 eq.) and diamine (S,S)-42 (683 mg, 2.20 mmol, 2.2 eq.) in

Et2O (3.5 mL) at −78 °C under Ar. The resulting solution was stirred at −30 °C for 5

min. Then, phenylisocyanate (262 mg, 2.20 mmol, 2.2 eq.) was added dropwise. The





column chromatography on silica with 98:2 CH2Cl2-Et2O as eluent gave amide (R,S)-



) (R,S)-235 7.1 min, (S,R)-235 14.0

min.



246









) (R,S)-235 7.4 min, (S,R)-235 13.3

min.




2.2 eq.), N-Boc 4-sulfonyl piperidine 234 (466 mg, 1.00 mmol, 1.0 eq.) and diamine






) (R,S)-235 7.4 min, (S,R)-235 14.5

min.




dropwise over 30 min via syringe pump to a stirred solution of N-Boc 4-chloro

piperidine 223 (219 mg, 1.00 mmol, 1.0 eq.) and diamine (S,S)-42 (683 mg, 2.20 mmol,

2.2 eq.) in Et2O (5.0 mL) at −78 °C under Ar. The resulting solution was stirred at −78

°C for 1 h. Then, phenylisocyanate (262 mg, 2.20 mmol, 2.2 eq.) was added dropwise.

The solution was allowed to warm slowly to rt over 2 h and stirred at rt for 16 h.




by flash column chromatography on silica with 98:2 CH2Cl2-Et2O as eluent gave amide



247


) (R,S)-235 7.2 min, (S,R)-235 13.9

min.




dropwise over 30 min via syringe pump to a stirred solution of N-Boc 4-chloro

piperidine 223 (219 mg, 1.00 mmol, 1.0 eq.) and diamine (S,S)-42 (683 mg, 2.20 mmol,

2.2 eq.) in Et2O (5.0 mL) at −40 °C under Ar. The resulting solution was stirred at −40

°C for 1 h. Then, phenylisocyanate (262 mg, 2.20 mmol, 2.2 eq.) was added dropwise.

The solution was allowed to warm slowly to rt over 2 h and stirred at rt for 16 h.




by flash column chromatography on silica with 98:2 CH2Cl2-Et2O as eluent gave amide

(R,S)-235 (208mg, 69%, 67:33 er by CSP-HPLC) as a pale yellow solid, CSP-HPLC:


) (R,S)-235 7.0 min, (S,R)-235 13.5

min.




dropwise over 30 min via syringe pump to a stirred solution of N-Boc 4-sulfonyl

piperidine 234 (350 mg, 0.75 mmol, 1.0 eq.) and (S,S)-42 (683 mg, 2.20 mmol, 2.2 eq.)










) (R,S)-235 7.3 min, (S,R)-235 12.7

min.


248




dropwise over 30 min via syringe pump to a stirred solution of N-Boc 4-sulfonyl

piperidine 234 (350 mg, 0.75 mmol, 1.0 eq.) and (S,S)-42 (683 mg, 2.20 mmol, 2.2 eq.)








235 (221mg, 98%, 58:42 er by CSP-HPLC) as a pale yellow solid, CSP-HPLC:


) (R,S)-235 7.1 min, (S,R)-235 13.7

min.




mL) was added dropwise over 30 min via syringe pump to a stirred solution of s-BuLi

(1.69 mL of a 1.3M solution in hexanes, 2.20 mmol, 2.2 eq.) and diamine (S,S)-42 (683

mg, 2.20 mmol, 2.2 eq.) in Et2O (3.5 mL) at −78 °C under Ar. The resulting solution

was stirred at −78 °C for 3 h. Then, phenylisocyanate (262 mg, 2.20 mmol, 2.2 eq.) was

added dropwise. The solution was allowed to warm slowly to rt over 2 h and stirred at rt

for 16 h. Saturated NH4Cl(aq) (10 mL) was added and the two layers were separated.




gave amide (R,S)-235 (210 mg, 70%, 62:38 er by CSP-HPLC) as a pale yellow solid,

CSP-HPLC: Chiracel OD (90:10 Hexane-iPrOH, 1.0 mLmin-1

) (R,S)-235 7.1 min,

(S,R)-235 13.8 min.



249



mL) was added dropwise over 30 min via syringe pump to a stirred solution of s-BuLi

(1.69 mL of a 1.3M solution in hexanes, 2.20 mmol, 2.2 eq.) and diamine (S,S)-42 (683

mg, 2.20 mmol, 2.2 eq.) in Et2O (3.5 mL) at −78 °C under Ar. The resulting solution

was stirred at −40 °C for 1 h. Then, phenylisocyanate (262 mg, 2.20 mmol, 2.2 eq.) was

added dropwise. The solution was allowed to warm slowly to rt over 2 h and stirred at rt

for 16 h. Saturated NH4Cl(aq) (10 mL) was added and the two layers were separated.




gave amide (R,S)-235 (210 mg, 71%, 60:40 er by CSP-HPLC) as a pale yellow solid,

CSP-HPLC: Chiracel OD (90:10 Hexane-iPrOH, 1.0 mLmin-1

) (R,S)-235 7.1 min,

(S,R)-235 13.6 min.


Sulfoxide → Magnesium Exchange Reactions

2-tert-Butyl (1S,5R)-1-methyl-2-azabicyclo[3.1.0]hexane-1,2-dicarboxylate (1S,5R)-

241

(S,R)-241

N

Boc

OMe

O


2.5 eq.) and sulfoxide syn-(R,R,SS)-225 (65 mg, 0.20 mmol, 1.0 eq., 99:1 er) in THF (8

mL) at rt for 1 min and methyl chloroformate (39 μL, 0.50 mmol, 2.5 eq.) gave the


EtOAc as eluent gave ester (S,R)-241 (43 mg, 89%, 99:1 er by CSP-HPLC) as a

colourless oil, RF (9:1 petrol-EtOAc) 0.3; IR (CDCl3) 2979, 1732 (C=O, CO2Me), 1682

(C=O, Boc), 1529, 1444, 1368, 1164, 908, 881, 732 cm-1

; 1

H NMR (400 MHz, CDCl3) δ

3.79 (ddd, J = 11.0, 9.5, 6.0 Hz, 1H, NCHAHB), 3.73 (s, 3H, OMe), 3.50 (br s, 1H,

NCHAHB), 2.25 (ddt, J = 13.0, 9.5, 6.0 Hz, 1H, CH), 2.08-2.02 (m, 1H, CH), 1.96 (dd,

J = 9.0, 5.5, Hz, 1H, CH), 1.98-1.87 (m, 1H, CH), 1.43 (s, 9H, CMe3), 1.02 (t, J = 5.5


250

Hz, 1H, CH); 13

C NMR (100.6 MHz, CDCl3) δ 171.5 (CO2Me) 155.5 (NCO2CMe3),

80.0 (CMe3), 52.1 (OMe), 50.2 (NCH2), 47.5 (NC), 31.0 (br, CH2), 28.4 (CH), 28.3

(CMe3), 26.4 (br, CH2); MS (ESI) m/z 264 [(M + Na)+, 100], 186 (20), 142 (30); HRMS

m/z calcd for C12H19NO4 (M + Na)+ 264.1203, found 264.1206 (+1.3 ppm error); [α]D

−121.05 (c 0.20 in CHCl3); CSP-HPLC: Chiracel OD (99:1 Hexane-iPrOH, 1.0 mLmin-

1) (S,R)-241 13.0 min, (R,S)-241 15.4 min.

2-tert-Butyl 1-methyl-2-azabicyclo[3.1.0]hexane-1,2-dicarboxylate rac-241

rac-241

N

Boc

OMe

O


1.5 eq.) and sulfoxide syn-rac-225 (65 mg, 0.20 mmol, 1.0 eq.,) in THF (8 mL) at rt for

1 min and methyl chloroformate (23 μL, 0.30 mmol, 1.5 eq.) gave the crude product.


gave ester rac-241 (24 mg, 50%) as a colourless oil.

tert-Butyl (1S,5R)-(phenylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

(S,R)-235

(S,R)-235

N

Boc

HN

O

Ph


2.5 eq.) and sulfoxide syn-(R,R,Ss)-225 (65 mg, 0.20 mmol, 1.0 eq., 99:1 er) in THF (8

mL) at rt for 1 min and phenylisocyanate (60 mg, 0.50 mmol, 2.5 eq.) gave the crude

product. Purification by flash column chromatography on silica with 98:2 CH2Cl2-Et2O

as eluent gave amide (S,R)-235 (31 mg, 67%, 99:1 er by CSP-HPLC) as a pale yellow

solid, mp 102-103 °C; RF (98:2 CH2Cl2-Et2O) 0.2; IR (CDCl3) 3408 (NH), 2979, 1689

(C=O), 1682 (C=O), 1529, 1444, 1368, 1164, 908, 732 cm-1

; 1

H NMR (400 MHz,

CDCl3) δ 8.32 (br s, 1H, NH), 7.49 (d, J = 8.0 Hz, 2H, o-Ph), 7.30 (t, J = 8.0 Hz, 2H, m-

Ph), 7.07 (d, J = 8.0 Hz, 1H, p-Ph), 3.75 (ddd, J = 11.5, 9.0, 6.5 Hz, 1H, NCHAHB), 3.66


251

(ddd, J = 11.5, 8.5, 5.5 Hz, 1H, NCHAHB), 2.24 (ddt, J = 13.0, 9.0, 6.5 Hz, 1H, CH),

2.17-2.12 (m, 1H,CH), 2.07 (dd, J = 9.0, 5.0 Hz, 1H, CH), 1.94 (dddd, J = 13.0, 8.5, 6.5,

1.5 Hz, 1H, CH), 1.42 (s, 9H, CMe3), 1.02 (t, J = 5.0 Hz, 1H, CH); 13

C NMR (100.6

MHz, CDCl3) δ 168.6 (PhNCO) 156.9 (NCO2CMe3), 137.8 (ipso-Ph), 128.9 (Ph), 123.9

(Ph), 119.3 (Ph), 81.2 (CMe3), 51.3 (NCH2), 50.6 (NC), 31.1 (CH), 28.1 (CMe3), 26.4

(CH2), 24.8 (CH2); MS (ESI) m/z 325 [(M + Na)+, 30], 303 [(M + H)

+, 100]; HRMS m/z

calcd for C17H22N2O3 (M + Na)+ 325.1523, found 325.1523 (−0.2 ppm error); ); [α]D

−58.6 (c 0.7 in CHCl3); CSP-HPLC: Chiracel OD (90:10 Hexane-iPrOH, 1.0 mLmin-1

)

(R,S)-235 7.4 min, (S,R)-235 14.5 min..

tert-Butyl 1-(phenylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate rac-235

rac-235

N

Boc

HN

O

Ph

Using general procedure D, s-BuLi (1.69 mL of a 1.3 M solution in hexanes, 2.20


TMEDA (255 mg, 2.20 mmol, 2.2 eq.) in Et2O (8 mL) and phenylisocyanate (262 mg,


chromatography on silica with 98:2 CH2Cl2-Et2O as eluent gave amide rac-235 (290

mg, 96%) as a pale yellow solid.

tert-Butyl (1S,5R)-1-(prop-2-en-1-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

(S,R)-230

(S,R)-230

N

Boc

i-PrMgCl (0.25 mL, 0.50 mmol, 2.5 eq.) was added dropwise to a stirred solution of

sulfoxide syn-(R,R,SS)-225 (65 mg, 0.20 mmol, 1.0 eq.) in THF (8 mL) at rt for 1 min at

rt under Ar. The resulting solution was stirred at rt for 1 min. Then, a solution of

CuBr.SMe2 (8 mg, 20 mol%, 0.2 eq.) in THF (1 mL) was added dropwise. The solution

was stirred at rt for 10 min. Then, allyl bromide (63 mg, 0.50 mmol, 2.5 eq.) was added


252

dropwise and the resulting solution was stirred at rt for 2 h. Saturated NH4Cl(aq) (7 mL)

was added and the two were layers separated. The aqueous layer was extracted with

Et2O (3 x 10 mL). The combined organic layers were dried (Na2SO4) and evaporated


chromatography on silica with 95:5 petrol-EtOAc as eluent gave allylated pyrrolidine

(S,R)-230 (31 mg, 69%) as a colourless oil, RF (95:5 petrol-EtOAc) 0.3; IR (CDCl3)

2941, 1685 (C=O), 1519, 1434, 1378, 1164, 1062, 910, 732 cm-1

; 1

H NMR (400 MHz,

CDCl3) δ 5.78 (dtd, J = 14.0, 7.0, 6.5 Hz, 1H, CH=CH2), 5.10-5.01 (m, 2H, =CH2), 3.62

(ddd, J = 11.0, 9.5, 6.0 Hz, 1H, NCHAHB), 3.38 (br s, 1H, NCHAHB), 3.21 (br s, 1H,

CH), 2.13-2.00 (m, 2H, CH), 1.82-1.75 (m, 1H, CH), 1.47 (s, 9H, CMe3), 1.40-1.34 (m,

1H, CH), 0.91 (dd, J = 8.5, 5.5 Hz, 1H, CH), 0.67 (t, J = 5.5 Hz, 1H, CH) ; 13

C NMR

(100.6 MHz, CDCl3) δ 156.0 (C=O), 135.2 (CH=CH2), 116.7 (CH=CH2), 79.3 (br,

CMe3), 50.0 (br, NCH2), 46.7 (NC), 37.5 (br, CH2CH=), 28.5 (CMe3), 25.9 (CH2), 23.3

(CH), 21.8 (CH2); MS (ESI) m/z 246 [(M + Na)+, 70], 168 (100); HRMS m/z calcd for

C13H21NO2 (M + Na)+ 246.1466, found 246.1465 (−0.5 ppm error); [α]D +2.4 (c 0.45 in

CHCl3); CSP-HPLC: Chiracel AD-H (99.5:0.5 Hexane-iPrOH, 0.3 mLmin-1

) (R,S)-230

11.0 min, (S,R)-230 11.8 min.

tert-Butyl 1-(prop-2-en-1-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate rac-230

rac-230

N

Boc

i-PrMgCl (0.15 mL, 0.30 mmol, 1.5 eq.) was added dropwise to a stirred solution of

sulfoxide syn-rac-225 (65 mg, 0.20 mmol, 1.0 eq.) in THF (8 mL) at rt for 1 min at rt

under Ar. The resulting solution was stirred at rt for 1 min. Then, a solution of

CuBr.SMe2 (8 mg, 20 mol%, 0.2 eq.) in THF (1 mL) was added dropwise. The solution

was stirred at rt for 10 min. Then, allyl bromide (38 mg, 0.30 mmol, 1.5 eq.) was added

dropwise and the resulting solution was stirred at rt for 2 h. Saturated NH4Cl(aq) (7 mL)


Et2O (3 x 10 mL). The combined organic layers were dried (Na2SO4) and evaporated



253

chromatography on silica with 95:5 petrol-EtOAc as eluent gave allylated pyrrolidine

rac-230 (26 mg, 58%) as a colourless oil.

tert-Butyl (1R,5R)-1-benzyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (R,R)-242

(R,R)-242

N

Boc

Ph

i-PrMgCl (0.25 mL of a 2.0 M solution in THF, 0.50 mmol, 2.5 eq.) was added to a

stirred solution of sulfoxide syn-(R,R,Ss)-225 (65 mg, 0.20 mmol, 1.0 eq., 99:1 er) in


solution of CuBr.SMe2 (8 mg, 0.04 mmol, 0.2 eq.) in THF (0.5 mL) and benzyl bromide

(89 mg, 0.50 mmol, 2.5 eq.) was added sequentially and the solution was stirred at rt for

2 h. Saturated NH4Cl(aq) (7 mL) was added and the two layers were separated. The




gave benzylated pyrrolidine (R,R)-242 (35 mg, 64%, 99:1 er by CSP-HPLC) as a

colourless oil, RF (4:1 petrol-Et2O) 0.2; IR (CDCl3) 2985, 2810, 1679 (C=O), 1559,

1487, 1378, 1201, 1164, 908, 732 cm-1

; 1

H NMR (400 MHz, CDCl3) δ 7.29-7.26 (m,

2H, Ph), 7.22-7.19 (m, 3H, Ph), 3.76 (br s, 1H, NCHAHB), 3.42-3.16 (br m, 2H,CH),

2.57 (d, J = 14.0 Hz, 1H, CH), 1.99 (tdd, J = 14.0, 7.0, 2.8 Hz, 1H, CH), 1.77-1.70 (m,

1H, CH), 1.50-1.44 (m, 1H, CH), 1.50 (s, 9H, CMe3), 0.98 (dd, J = 9.0, 5.0 Hz, 1H, CH)

0.73 (t, J = 5.0 Hz, 1H, CH); 13

C NMR (100.6 MHz, CDCl3) δ 153.9 (C=O), 139.4

(ipso-Ph), 129.4 (Ph), 128.2 (Ph), 126.2 (Ph), 79.4 (CMe3), 48.4 (br, NCH2), 43.5 (br,

NC), 41.0 (br PhCH2), 32.6 (br, CH), 28.6 (CMe3), 26.1 (CH2), 23.7 (CH2); MS (ESI)

m/z 296 [(M + Na)+, 70], 218 (100); HRMS m/z calcd for C17H24NO2 (M + Na)

+

296.1621, found 296.1611 (+3.2 ppm error); [α]D −13.6 (c 0.2 in CHCl3); CSP-HPLC:


) (R,R)-242 5.6 min, (S,S)-242 6.6 min.


254

tert-Butyl 1-benzyl-2-azabicyclo[3.1.0]hexane-2-carboxylate rac-242

rac-242

N

Boc

Ph

i-PrMgCl (0.25 mL of a 2.0 M solution in THF, 0.50 mmol, 2.5 eq.) was added to a

stirred solution of sulfoxide syn-rac-225 (65 mg, 0.20 mmol, 1.0 eq., 99:1 er) in THF (8

mL) at rt under Ar. The resulting solution was stirred at rt for 1 min. Then, a solution of

CuBr.SMe2 (8 mg, 0.04 mmol, 0.2 eq.) in THF (0.5 mL) and benzyl bromide (89 mg,

0.50 mmol, 2.5 eq.) was added sequentially and the solution was stirred at rt for 2 h.




by flash column chromatography on silica with 4:1 petrol-Et2O as eluent gave

benzylated pyrrolidine rac-242 (32 mg, 59%) as a colourless oil.

2-tert-Butyl (1S,5R)-1-phenyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (1S,5R)-243

(1S,5R)-243

N

Boc

Ph

Using general procedure K, i-PrMgCl (0.25 mL of a 2.0 M solution in THF, 0.50 mmol,

2.5 eq.) and sulfoxide syn-(R,R,SS)-225 (65 mg, 0.20 mmol, 1.0 eq.) in THF (8 mL) and

ZnCl2 (0.12 mL of a 1.0 M solution in Et2O, 0.12 mmol, 0.6 eq.), Pd(OAc)2 (3 mg, 0.01

mmol, 0.05 eq.), t-Bu3PH.BF4 (3.5 mg, 0.012 mmol, 0.06 eq.) and bromobenzene (39


chromatography on silica with 98:2 CH2Cl2-petrol as eluent gave arylated pyrrolidine

(1S,5R)-243 (35 mg, 68%, 99:1 er by CSP-HPLC) as a colourless oil, RF (98:2 CH2Cl2-

petrol) 0.3; IR (CDCl3) 2874, 2791, 1681 (C=O) 1540, 1521, 1444, 1368, 908, 732 cm-

1; 1

H NMR (400 MHz, CDCl3) δ 7.31-7.24 (m, 4H, Ph), 7.21-7.16 (m, 1H, Ph), 3.90

(ddd, J = 11.5, 9.5, 6.0 Hz, 1H, NCHAHB), 3.61 (ddd, J = 11.5, 9.0, 6.0 Hz, 1H,

NCHAHB), 2.32 (ddt, J = 12.5, 9.5, 6.0 Hz, 1H, CH), 1.97 (dddd, J = 12.5, 9.0, 6.0, 1.0


255

Hz, 1H, CH), 1.81 (dd, J = 9.0, 5.5 Hz, 1H, CH), 1.62-1.56 (m, 1H, CH), 1.22 (br s, 9H,

CMe3), 1.02 (t, J = 5.5 Hz, 1H, CH); 13

C NMR (100.6 MHz, CDCl3) δ 154.7 (C=O),

133.6 (ipso-Ph), 132.7 (Ph), 127.9 (Ph), 125.9 (Ph), 79.4 (CMe3), 50.1 (NCH2), 49.7

(NC), 30.3 (NCCH), 28.2 (CMe3), 26.7 (CH2), 22.3 (CH2); MS (ESI) m/z 282 [(M +

Na)+, 100], 204 (30); HRMS m/z calcd for C16H21NO2 (M + Na)

+ 282.1465, found

282.1470 (−2.1 ppm error); [α]D +8.2 (c 0.65 in CHCl3); CSP-HPLC: Chiracel AD-H


) (1S,5R)-36 8.5 min, (1S,5R)-36 10.0 min.

tert-Butyl 1-phenyl-2-azabicyclo[3.1.0]hexane-2-carboxylate rac-243

rac-243

N

Boc

Ph


1.5 eq.) and sulfoxide syn-rac-225 (65 mg, 0.20 mmol, 1.0 eq.) in THF (8 mL) and


mmol, 0.05 eq.), t-Bu3PH.BF4 (3.5 mg, 0.012 mmol, 0.06 eq.) and bromobenzene (22


chromatography on silica with 98:2 CH2Cl2-petrol as eluent gave arylated pyrrolidine

rac-243 (20 mg, 55%) as a colourless oil.

tert-Butyl 1-[2-methoxyphenyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate (1S,5R)-

244

(1S,5R)-244

N

Boc

OMe




mmol, 0.05 eq.), t-Bu3PH.BF4 (3.5 mg, 0.012 mmol, 0.06 eq.) and methyl 2-

bromoanisole (45 mg, 0.24 mmol, 1.20 eq.) gave the crude product. Purification by

flash column chromatography on silica with 7:3 petrol-Et2O as eluent gave arylated


256

pyrrolidine (1S,5R)-244 (39 mg, 68%) as a colourless oil, RF (7:3 petrol-Et2O) 0.2; IR

(CDCl3) 2875, 2782, 1685 (C=O), 1421, 1444, 1368, 913, 742 cm-1

; 1

H NMR (400

MHz, CDCl3) δ 7.30 (br d, J = 7.5 Hz, 1H, Ar), 7.22 (td, J = 7.5, 2.0 Hz, 1H, Ar), 6.88

(br t, J = 7.5 Hz, 1H, Ar), 6.83 (br d, J = 7.5 Hz, 1H, Ar), 3.97 (td, J = 12.0, 4.5 Hz, 1H,

NCHAHB), 3.84 (s, 3H, OMe), 3.60-3.53 (br m, 1H, NCHAHB), 2.37 (dddd, J = 12.5,

7.5, 4.5, 1.5 Hz, 1H, CH), 1.97-1.90 (m, 1H, CH), 1.60-1.53 (m, 2H, CH), 1.22 (br s,

9H, CMe3), 0.90 (t, J = 4.0 Hz, 1H, CH); 13

C NMR (100.6 MHz, CDCl3) δ 158.8

(C=O), 155.5 (ipso-C6H4OMe), 131.6 (Ar), 128.7 (Ar), 128.2 (ipso-Ar), 119.6 (Ar),

110.1 (Ar), 79.0 (CMe3), 55.5 (OMe), 50.5 (NCH2), 46.8 (NC), 28.3 (CMe3), 27.3 (br,

CH), 26.9 (CH2), 22.8 (CH2); MS (ESI) m/z 312 [(M + Na)+, 100], 234 (70), 190 (30);

HRMS m/z calcd for C17H23NO3 (M + Na)+ 321.1572, found 312.1570 (−0.5 ppm

error); [α]D −6.9 (c 0.65 in CHCl3); CSP-HPLC: Chiracel AD-H (99:1 Hexane-iPrOH,

0.5 mLmin-1

) (1S,5R)-244 7.5 min, (1R,5S)-244 8.3 min.

tert-Butyl 1-[2-methoxyphenyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate rac-244

rac-244

N

Boc

OMe





bromoanisole (26 mg, 0.14 mmol, 0.7 eq.) gave the crude product. Purification by flash

column chromatography on silica with 7:3 petrol-Et2O as eluent gave arylated

pyrrolidine rac-244 (19 mg, 48%) as a colourless oil.

tert-Butyl 1-[2-(methoxycabronyl)phenyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate

(1S,5R)-245

(1S,5R)-245

N

Boc

CO2Me


257


2.5 eq.), sulfoxide syn-(R,R,SS)-225 (65 mg, 0.20 mmol, 1.0 eq.) in THF (8 mL), ZnCl2

(0.12 mL of a 1.0 M solution in Et2O, 0.12 mmol, 0.6 eq.), Pd(OAc)2 (3 mg, 0.01


bromobenzoate (51 mg, 0.24 mmol, 1.2 eq.) gave the crude product. Purification by


pyrrolidine (1S,5R)-245 (47 mg, 74%) as a colourless oil, RF (7:3 petrol-Et2O) 0.1; IR

(CDCl3) 2874, 1726 (C=O, CO2Me), 1679 (C=O, Boc), 1532, 1454, 1268, 908, 732 cm-

1; 1

H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 8.0, 1.5 Hz, 1H, o-C6H4CO2Me), 7.38 (br

t, J = 8.0 Hz 1H, p-C6H4CO2Me), 7.32-7.25 (m, 2H, Ar), 3.87 (s, 3H, OMe), 3.76 (dt, J

= 11.0, 4.0 Hz, 1H, NCHAHB), 3.37-3.30 (br m, 1H, NCHAHB), 2.58-2.49 (m, 1H, CH),

2.00 (dtd, J = 12.0, 9.0, 4.0 Hz, 1H, CH), 1.79-1.74 (m, 1H, CH), 1.81 (dd, J = 9.0, 5.5

Hz, 1H, CH), 1.07 (br s, 9H, CMe3), 0.90 (t, J = 5.5 Hz, 1H, CH); 13

C NMR (100.6

MHz, CDCl3) δ 169.3 (CO2Me), 155.9 (NCO2CMe3), 134.4 (ipso-Ar), 132.1 (Ar), 130.5

(br, Ar), 128.9 (Ar), 128.8 (Ar), 126.5 (Ar), 79.4 (CMe3), 52.0 (OMe), 48.7 (NC), 48.6

(NCH2), 30.0 (CH), 27.9 (CMe3), 25.6 (CH2), 18.5 (CH2); MS (ESI) m/z 340 [(M +

Na)+, 100], 318[(M + H)

+, 40], 262 (40), 218 (40); HRMS m/z calcd for C18H23NO4 (M

+ Na)+ 340.1518, found 340.1519 (+0.4 ppm error); [α]D −46.4 (c 1.00 in CHCl3); CSP-

HPLC: Chiracel AD-H (99:1 Hexane-iPrOH, 1.0 mLmin-1

) (1S,5R)-245 9.7 min,

(1R,5S)-245 15.8 min.

tert-Butyl 1-[2-(methoxycabronyl)phenyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate

rac-245

rac-245

N

Boc

CO2Me





bromobenzoate (30 mg, 0.14 mmol, 0.7 eq.) gave the crude product. Purification by


258



2-tert-Butyl (1S,5R)-1-(thiophen-3-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

(1S,5R)-246

(1S,5R)-246

N

Boc S

H4

H5

H2




mmol, 0.05 eq.), t-Bu3PH.BF4 (3.5 mg, 0.012 mmol, 0.06 eq.) and 3-bromothiophene

(23 μL, 0.24 mmol, 1.2 eq.) gave the crude product. Purification by flash column

chromatography on silica with 99:1-98:2 CH2Cl2-Et2O as eluent gave arylated

pyrrolidine (1S,5R)-246 (38 mg, 72%) as a colourless oil, RF (98:2 CH2Cl2-Et2O) 0.5;

IR (CDCl3) 2910, 2874, 1675 (C=O), 1555, 1532, 1268, 908, 732 cm-1

; 1

H NMR (400

MHz, CDCl3) δ 7.22 (dd, J = 5.0, 3.0 Hz, 1H, H5), 6.98 (dd, J = 5.0, 1.5 Hz 1H, H

4),

6.94 (dd, J = 3.0, 1.5 Hz, 1H, H2), 3.86 (ddd, J = 11.5, 9.5, 6.0 Hz, 1H, NCHAHB), 3.55

(ddd, J = 11.5, 9.0, 6.0 Hz, 1H, NCHAHB), 2.34-2.25 (m, 1H, CH), 1.93 (dddd, J = 13.0,

9.0, 6.0, 1.5 Hz, 1H, CH), 1.68-1.60 (m, 2H, CH), 1.28 (br s, 9H, CMe3), 1.04 (t, J = 5.0

Hz, 1H, NCCHAHB); 13

C NMR (100.6 MHz, CDCl3) δ 156.2 (C=O), 132.6 (ipso-Ar),

126.4 (Ar), 125.0 (br, Ar), 118.7 (Ar), 79.4 (CMe3), 49.9 (NC), 46.6 (NCH2), 30.8 (br,

CH), 28.2 (CMe3), 26.5 (CH2), 23.5 (CH2); MS (ESI) m/z 288 [(M + Na)+, 100], 210

(40); HRMS m/z calcd for C14H19NO2S (M + Na)+ 288.1029, found 288.1027 (+0.6 ppm

error); [α]D −42.0 (c 0.5 in CHCl3); CSP-HPLC: Chiracel OD-H (99:1 Hexane-iPrOH,

1.0 mLmin-1

) (S,R)-246 7.7 min, (R,S)-246 8.6 min.

2-tert-Butyl 1-(thiophen-3-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate rac-246

rac-246

N

Boc S

H4

H5

H2


259




mmol, 0.05 eq.), t-Bu3PH.BF4 (3.5 mg, 0.012 mmol, 0.06 eq.) and 3-bromothiophene

(23 μL, 0.24 mmol, 1.2 eq.) gave the crude product. Purification by flash column

chromatography on silica with 99:1-98:2 CH2Cl2-Et2O as eluent gave arylated


tert-Butyl 3-(hydroxymethyl)-1-[(4-methylphenyl)sulfanyl]-2-

azabicyclo[3.1.0]hexane-2-carboxylate (1R,5R)-254190,191

(R,R)-254

NBoc

S

Trifluoroacetic anhydride (318 μL, 2.25 mmol, 3.0 eq.) was added dropwise to a stirred

suspension of sulfoxide syn-(R,R,SS)-225 (240 mg, 0.75 mmol, 1.0 eq.) and NaI (225

mg, 1.50 mmol, 2.0 eq.) in acetone (9 mL) at −40 °C under Ar. The resulting solution

was stirred at −40 °C for 10 min. Then, saturated Na2SO3(aq) (5 mL) and saturated

NaHCO3(aq) (5 mL) were added sequentially and the two layers were separated. The

aqueous layer was extracted with Et2O (3 x 10 mL) The combined organic layers were



eluent gave sulfide 254 (228 mg, 99%) as a pale yellow oil, RF (8:2 petrol-EtOAc) 0.4;

IR (film) 2948, 2912, 2877, 1656 (C=O), 1557, 1552, 1348, 1278, 912, 732 cm-1

; 1

H

NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.0 Hz, 2H, o-C6H4Me), 7.11 (d, J = 8.0 Hz, 2H,

m-C6H4Me), 3.52-3.48 (m, 2H, NCH2), 2.34 (s, 3H, Me), 2.11-2.00 (m, 1H, CH), 1.82-

1.72 (m, 2H, CH), 1.63 (dd, J = 9.0, 5.0 Hz, 1H, CH), 1.52 (s, 9H, CMe3), 1.13 (t, J =

5.0 Hz, 1H, CHAHB); 13


C6H4S), 132.1 (ipso-C6H4Me), 132.0 (Ar), 129.5 (Ar), 80.0 (CMe3), 53.7 (NC), 51.2

(NCH2), 29.1 (CH2), 28.6 (CMe3), 28.4 (CH), 26.8 (CH2), 21.2 (Me); MS (ESI) m/z 328

[(M + Na)+, 100], 306 [(M + H)

+, 25]; HRMS m/z calcd for C17H23NO2S (M + Na)

+

328.1347, found 328.1347 (0.0 ppm error); [α]D –45.8 (c 0.6 in CHCl3).


260


azabicyclo[3.1.0]hexane-2-carboxylate cis-(1R,3S,5R)-255

256

NBoc

HOS

cis-255

NBoc

HOS

O


dropwise to a stirred solution of sulfide 254 (228 mg, 0.75 mmol, 1.0 eq.) and (+)-

sparteine surrogate (191 mg, 0.98 mmol, 1.3 eq.) in Et2O (5 mL) at −78 °C under Ar.

The resulting solution was stirred at −78 °C for 5 min. Then, CO2 was bubbled through

the solution for 10 min and the resulting solution allowed to warm to rt. Water (5 mL)

and 1 M NaOH(aq) (10 mL) were added and the two layers were separated. The aqueous

layer was acidified (pH 1) with 2 M HCl(aq) and extracted with Et2O (3 × 10 mL). The


give the crude product which contained a 92:8 mixture (by 1H NMR spectroscopy) of

diastereoisomeric acids 256 which required no further purification: 1H NMR (400 MHz,

CDCl3) δ 8.50 (br s, 1H, OH), 7.28 (d, J = 8.0 Hz, 2H, o-C6H4Me), 7.12 (d, J = 8.0 Hz,

2H, m-C6H4Me), 4.55 (br s, 0.92H, NCH), 4.21 (dd, J = 10.0, 5.0 Hz, 0.08H, NCH),

2.68 (br s, 0.08H, 1H, CH), 2.54-2.50 (br m, 0.92H, 1H, CH), 2.34 (s, 2.76H, Me), 2.33

(s, 0.24, Me), 2.07 (dd, J = 13.0, 4.5 Hz, 0.08H, CHAHB), 1.99 (dd, J = 13.0, 7.0 Hz,

0.92H, CHAHB), 1.78-1.76 (m, 1H, CH), 1.70-1.65 (m, 1H, CH), 1.52-1.43 (m, 1H,

CH), 1.47 (br s, 9H, CMe3). Borane dimethyl sulfide complex (77 μL, 0.82 mmol, 1.3

eq.) was added dropwise to a stirred solution of the crude acids 256 (218 mg, 0.63

mmol, 1.0 eq.) in THF (5 mL) at 0 °C under Ar. After gas evolution ceased, the

resulting solution was stirred and heated at 66 °C for 1 h. Then, the solution was cooled

to rt and MeOH (5 mL) was added dropwise. The solvent was evaporated under reduced


silica with 9:1-8:2 petrol-EtOAc as eluent gave alcohol cis-(1R,3S,5R)-255 (211 mg,

84% over two steps) as a colourless oil, RF (8:2 petrol-EtOAc) 0.3; IR (film) 3315 (OH),

2892, 2877, 1688 (C=O), 1565, 1488, 1258, 912, 732 cm-1

; 1


δ 7.31 (d, J = 8.0 Hz, 2H, o-C6H4Me), 7.14 (d, J = 8.0 Hz, 2H, m-C6H4Me), 5.32 (br s,

1H, OH), 4.03-3.97 (m, 1H, NCH), 3.52-3.42 (m, 2H, CH2OH), 2.35 (s, 3H, Me), 2.18-

2.11 (m, 1H, CH), 1.64-1.60 (m, 2H, CH), 1.57 (s, 9H, CMe3), 1.33-1.25 (m, 1H, CH),


261

1.16-1.14 (m, 1H, CH); 13


C6H4S), 133.1 (Ar), 131.2 (ipso-C6H4Me), 129.8 (Ar), 81.1 (CMe3), 70.4 (NCH), 65.0

(CH2OH), 57.0 (NC), 34.2 (CH2), 31.9 (CH2), 28.4 (CMe3), 25.7 (CH), 21.1 (Me); MS

(ESI) m/z 358 [(M + Na)+, 90], 336 [(M + H)

+, 40], 280 (100); HRMS m/z calcd for

C18H25NO3S (M + Na)+ 358.1447, found 358.1443 (+1.1 ppm error); [α]D –139.8 (c 0.7

in CHCl3).


azabicyclo[3.1.0]hexane-2-carboxylate cis-rac-255 and tert-Butyl 3-

(hydroxymethyl)-1-[(4-methylphenyl)sulfanyl]-2-azabicyclo[3.1.0]hexane-2-

carboxylate trans-rac-255

cis-256

NBoc

HOS

cis-rac-255

NBoc

HOS

pTol

O

trans-rac-255

NBoc

HOS

pTol

t rans-256

NBoc

HOS

pTol

O

pTol


dropwise to a stirred solution of sulfide rac-254 (1.10 g, 3.61 mmol, 1.0 eq.) and

TMEDA (701 μL, 4.69 mmol, 1.3 eq.) in Et2O (15 mL) at −78 °C under Ar. The

resulting solution was stirred at −78 °C for 5 min. Then, CO2 was bubbled through the

solution for 10 min and the resulting solution allowed to warm to rt. Water (5 mL) and

1 M NaOH(aq) (10 mL) were added and the two layers were separated. The aqueous

layer was acidified (pH 1) with 2 M HCl(aq) and extracted with Et2O (3 × 10 mL). The


give the crude product which contained a 68:32 mixture (by 1H NMR spectroscopy) of

diastereoisomeric acids 256 which required no further purification. Borane dimethyl

sulfide complex (0.36 mL, 3.72 mmol, 1.3 eq.) was added dropwise to a stirred solution

of the crude acids 256 (1.00 g, 2.86 mmol, 1.0 eq.) in THF (20 mL) at 0 °C under Ar.

After gas evolution ceased, the resulting solution was stirred and heated at 66 °C for 1

h. Then, the solution was cooled to rt and MeOH (5 mL) was added dropwise. The

solvent was evaporated under reduced pressure to give the crude product. Purification

by flash column chromatography on silica with 9:1-8:2 petrol-EtOAc as eluent gave

alcohol cis-rac-255 (615 mg, 51% over two steps) as a colourless oil and trans-rac-255

(258 mg, 21% over two steps) as a colourless oil, RF (8:2 petrol-EtOAc) 0.2; IR (film)


262

3312 (OH), 2901, 2896, 2867, 1698 (C=O), 1495, 1487, 1305, 1132, 915, 730 cm-1

; 1

H

NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.0 Hz, 2H, o-C6H4Me), 7.17 (d, J = 8.0 Hz, 2H,

m-C6H4Me), 3.88-3.82 (m, 1H, NCH), 3.30 (br s, 1H, OH), 3.25-3.23 (m, 1H,

CHAHBOH), 2.97 (t, J = 8.5 Hz, 1H, CHAHBOH) 2.36 (s, 3H, Me), 2.03-1.98 (m, 1H,

CH), 1.76-1.64 (m, 3H, CH), 1.57 (s, 9H, CMe3), 1.04 (t, J = 5.5 Hz, 1H, CH); 13

C

NMR (100.6 MHz, CDCl3) δ 152.0 (C=O), 138.8 (ipso-C6H4S), 134.5 (Ar), 130.5

(ipso-C6H4Me), 129.8 (Ar), 81.3 (CMe3), 66.5 (CH2OH), 64.7 (NCH), 55.5 (NC), 29.8

(CH2), 29.7 (CH2), 28.4 (CMe3), 27.4 (CH), 21.2 (Me); MS (ESI) m/z 358 [(M + Na)+,

100], 336 [(M + H)+, 30], 280 (100); HRMS m/z calcd for C18H25NO3S (M + Na)

+

358.1447, found 358.1449 (−0.5 ppm error).

tert-Butyl 3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate cis-

(1S,3S,5R)-253

cis-253

NBoc

HO

Raney®

-Nickel 2400 (1.5 mL of a 50% suspension in water) was added dropwise to a

stirred solution of alcohol cis-(1R,3S,5R)-255 (211 mg, 0.63 mmol, 1.0 eq.) in 1:2 THF-

EtOH (6 mL) at rt under Ar. The resulting solution was stirred at rt for 5 h. Then,

CH2Cl2 (10 mL) and MgSO4 were added and the solids were removed by filtration

through Celite®. The filtrate was evaporated under reduced pressure to give the crude

product. Purification by flash column chromatography on silica with 9:1-8:2 petrol-

acetone as eluent gave alcohol cis-(1S,3S,5R)-253 (98 mg, 73%) as a colourless oil, RF

(8:2 petrol-acetone) 0.3; 1

H NMR (400 MHz, CDCl3) δ 4.32-4.28 (br m, 1H, CH), 3.51-

3.43 (m, 4H, CH + OH), 2.46 (dddd, J = 13.5, 11.0, 6.5, 1.0 Hz, 1H, CH), 1.58-1.52 (m,

1H, CH), 1.50 (s, 9H, CMe3), 1.50-1.47 (m, 1H, CHAHB), 0.80 (dtd, J = 9.0, 6.0, 1.0 Hz,

1H, CH), 0.43-0.40 (br m, 1H, CH); 13

C NMR (100.6 MHz, CDCl3) (rotamers) δ 156.6

(br, C=O), 80.6 (CMe3), 80.3 (CMe3), 67.6 (br, NCHCH2OH), 54.5 (CH2OH), 38.8

(NCH), 37.4 (CH2), 32.0 (CH), 30.6 (CH2), 28.4 (CMe3), 28.4 (CMe3), 16.9 (CH2), 14.7

(CH2); MS (ESI) m/z 236 [(M + Na)+, 100], 213 [(M + H)


C11H19NO3 (M + Na)+ 236.1263, found 236.1263 (0.0 ppm error); [α]D +6.6 (c 0.5 in

CHCl3) [lit.184

, [α]D +12.0 (c 0.75 in CHCl3)]. Spectroscopic data consistent with those



263

5.5 Experimental for Chapter Four

2,2-Dimethyl-1-azetidinyl-1-ylpropan-1-thione 101102

N

101

S

Trimethylacetyl chloride (7.21 mL, 58.6 mmol, 1.1 eq.) was added to a stirred solution

of azetidine hydrochloride (5.00 g , 53.3 mmol, 1.0 eq.) and Et3N (37.1 mL, 266 mmol,

5.0 eq.) in CH2Cl2 (75 mL) at 0 °C. The resulting solution was allowed to warm to rt

and stirred at rt for 16 h. Then, 1 M HCl(aq) (15 mL) was added and the two layers

were separated. The aqueous layer was extracted with CH2Cl2 (3 x 30 mL). The

combined organic layers were dried (MgSO4) and evaporated under reduce pressure to

give the crude N-pivaloyl azetidine. The residue was dissolved in pyridine (150 mL)

and phosphorous(V) sulfide (14.80 g, 66.6 mmol, 1.25 eq.) was added. The resulting

solution was heated to 75 °C for 6 h. The solution was allowed to cool to rt and then

poured into 1 M HCl(aq) (150 mL). 1 M HCl(aq) was added until pH 3 was obtained. The

resulting solution was stirred at rt for 2 h and then extracted with CH2Cl2 (3 × 50 mL).

The combined organic extracts were washed with 1 M HCl(aq) (50 mL), water (50 mL)

and brine (50 mL), dried (MgSO4) and evaporated under reduced pressure to give the

crude product. Purification by flash column chromatography on silica with 8:2-7:3

petrol-Et2O as eluent gave thioamide 101 (6.40 g, 78%) as a yellow oil, RF (8:2 petrol-

Et2O) 0.2; 1H NMR (400 MHz, CDCl3) δ 4.51 (br t, J = 7.5 Hz, 2H, NCH2), 4.29 (br t, J

= 7.5 Hz, 2H, NCH2), 2.33-2.25 (m, 2H, CH2), 1.36 (s, 9H, CMe3); 13

C NMR (100.6

MHz, CDCl3) δ 209.1 (C=S), 56.6 (NCH2), 56.0 (NCH2) 43.1 (CMe3), 29.8 (CMe3),

14.6 (CH2). Spectroscopic data consistent with those reported in the literature.102



264

1-[(2R)-2-[(S)-Hydroxy(phenyl)methyl]azetidin-1-yl]-2,2-dimethylpropane-1-thione

anti-(S,R)-273 and 1-[(2R)-2-[(R)-hydroxy(phenyl)methyl]azetidin-1-yl]-2,2-

dimethylpropane-1-thione syn-(R,R)-273

N OH

PhH

N OH

PhH

syn-(R,R)-273ant i-(S,R)-273

S S

Using general procedure L, s-BuLi (0.46 mL of a 1.3 M solution in hexanes, 0.6 mmol,

1.2 eq.), N-thiopivaloyl azetidine 101 (79 mg, 0.5 mmol, 1.0 eq.) and (−)-sparteine (0.14

mL, 0.6 mmol, 1.2 eq.) in Et2O (5 mL) and benzaldehyde (76 μL, 0.75 mmol, 1.5 eq.)

gave the crude product which contained an 86:14 mixture of alcohols syn-(R,R)-273 and

anti-(S,R)-273 by 1H NMR spectroscopy. Purification by flash column chromatography

on silica with 9:1-8:2 petrol-EtOAc as eluent gave alcohol anti-(S,R)-273 (12 mg, 9%,

58:42 er by CSP-HPLC) as a white solid, mp 151-153 °C; RF (4:1 petrol-EtOAc) 0.3; IR

(CHCl3) 3203 (OH), 2921, 1441, 1414, 1341, 1242, 1126, 996, 980, 731 cm−1

; 1H NMR

(400 MHz, CDCl3) δ 7.44 (d, J = 8.0 Hz, 2H, o-Ph), 7.36 (t, J = 8.0 Hz, 2H, m-Ph), 7.31

(d, J = 8.0 Hz, 1H, Ph), 5.46 (br d, J = 5.0 Hz 1H, CHO), 5.28-5.24 (m, 1H, NCH), 4.56

(d, J = 5.0 Hz, 1H, OH), 4.21 (td, J = 10.0, 5.0 Hz, 1H, NCHAHB), 3.92-3.85 (m, 1H

NCHAHB), 2.35-2.26 (m, 1H, CHAHB), 2.16-2.08 (m, 1H, CHAHB), 1.30 (s, 9H, CMe3);

13C NMR (100.6 MHz, CDCl3) δ 211.1 (C=S), 139.6 (ipso-Ph), 128.2 (Ph), 127.7 (Ph),

126.7 (Ph), 73.7 (OCH or NCH), 73.5 (OCH or NCH), 56.1 (NCH2), 43.4 (CMe3) 29.5

(CMe3), 17.2 (CH2); MS (ESI) m/z 286 [(M + Na)+, 100], 264 [(M + H)

+, 30], 208

(100); HRMS m/z calcd for C15H21NO3 (M + Na)+ 286.1414, found 286.1414 (0.0 ppm

error); [α]D +40.9 (c 0.65 in CHCl3); CSP-HPLC: Chiracel AD-H (95:5 Hexane-iPrOH,

1.0 mL min-1

) (S,R)-273 7.4 min, (R,S)-273 10.0 min and alcohol syn-(R,R)-273 (99 mg,

75%, 75:25 er by CSP-HPLC) as a white solid, mp 109-111 °C (lit.,102

116-117 °C); RF

(4:1 petrol-EtOAc) 0.2; 1

H NMR (400 MHz, CDCl3) δ 7.45-7.43 (m, 2H, Ph), 7.39-7.29

(m, 3H, Ph), 5.32 (d, J = 7.5 Hz, 1H, CHOH), 5.22 (dddd, J = 9.0, 7.5, 5.0, 1.5 Hz, 1H,

NCH), 5.17 (br s, 1H, OH), 4.31 (td, J = 10.0, 5.0 Hz, 1H, NCHAHB), 4.20-4.13 (m, 1H,

NCHAHB), 2.20 (dddd, J = 12.0, 10.0, 9.0, 7.5 Hz, 1H, CHAHB), 1.86 (ddt, J = 12.0, 9.5,

5.0 Hz, 1H, CHAHB), 1.35 (s, 9H, CMe3); 13

C NMR (100.6 MHz, CDCl3) δ 212.3

(C=S), 139.9 (ipso-Ph), 128.3 (Ph), 128.1 (Ph), 127.3 (Ph), 76.3 (OCH or NCH), 73.8


265

(OCH or NCH), 56.0 (NCH2), 43.6 (CMe3), 29.6 (CMe3), 18.3 (CH2); [α]D +74.8 (c

0.75 in CHCl3); CSP-HPLC: Chiracel AD-H (95:5 Hexane-iPrOH, 1.0 mL min-1

) (R,R)-

273 17.8 min, (S,S)-273 20.4 min. Spectroscopic data for syn-rac-273 is consistent with




stirred solution of N-thiopivaloyl azetidine 101 (79 mg, 0.50 mmol, 1.0 eq.) in Et2O (5


(−)-sparteine (0.14 mL, 0.60 mmol, 1.2 eq.) was added and the resulting solution was

stirred for 15 min. The solution was then cooled to −78 °C and stirred at −78 °C for 30

min. Benzaldehyde (38 μL, 0.38 mmol, 1.5 eq.) was added dropwise. The resulting

solution was stirred at −78 °C for 10 min and 1 M HCl(aq) was added. The two layers

were separated and the aqueous layer was extracted with Et2O (3 x 10 mL). The

combined organic layers were dried (MgSO4) and evaporated under reduced pressure to

give the crude product which contained an 81:19 mixture of alcohols syn-(R,R)-273 and

anti-(S,R)-273 by 1H NMR spectroscopy. Purification by flash column chromatography

on silica with 9:1-8:2 petrol-EtOAc as eluent gave alcohol anti-(S,R)-273 (9 mg, 7%,

59:41 er by CSP-HPLC) as a white solid, CSP-HPLC: Chiracel AD-H (95:5 Hexane-

iPrOH, 1.0 mL min-1

) (S,R)-273 7.5 min, (R,S)-273 10.1 min and alcohol syn-(R,R)-273

(76 mg, 57%, 71:29 er by CSP-HPLC) as a white solid, CSP-HPLC: Chiracel AD-H

(95:5 Hexane-iPrOH, 1.0 mL min-1

) (R,R)-273 18.2 min, (S,S)-273 20.2 min.




stirred solution of N-thiopivaloyl azetidine 101 (79 mg, 0.5 mmol, 1.0 eq.) and (−)-

sparteine (0.14 mL, 0.6 mmol, 1.2 eq.) in Et2O (5 mL) at −78 °C under Ar. The

resulting solution was stirred at −78 °C for 30 min. Then, the solution was warmed to

−50 °C and stirred for 1 h. Benzaldehyde (76 μL, 0.75 mmol, 1.5 eq.) was added

dropwise and the resulting solution was stirred at −50 °C for 10 min. Then, 1 M HCl(aq)

was added. The two layers were separated and the aqueous layer was extracted with

Et2O (3 x 10 mL). The combined organic layers were dried (MgSO4) and evaporated



266

alcohols syn-(R,R)-273 and anti-(S,R)-273 by 1H NMR spectroscopy. Purification by

flash column chromatography on silica with 9:1-8:2 petrol-EtOAc as eluent gave

alcohol anti-(S,R)-273 (17 mg, 13%, 58:42 er by CSP-HPLC) as a white solid, CSP-

HPLC: Chiracel AD-H (95:5 Hexane-iPrOH, 1.0 mL min-1

) (S,R)-273 7.5 min, (R,S)-

273 10.2 min and alcohol syn-(R,R)-273 (108 mg, 82%, 68:32 er by CSP-HPLC) as a

white solid, CSP-HPLC: Chiracel AD-H (95:5 Hexane-iPrOH, 1.0 mL min-1

) (R,R)-273

18.4 min, (S,S)-273 20.9 min.
















) (S,R)-273 7.5 min, (R,S)-



) (R,R)-273

18.2 min, (S,S)-273 20.8 min.









267









) (S,R)-273 7.5 min, (R,S)-



) (R,R)-273

18.5 min, (S,S)-273 20.5 min.







−30 °C and stirred for 1 h. The solution was then cooled to −78 °C and stirred at −78

°C for 30 min. Benzaldehyde (76 μL, 0.75 mmol, 1.5 eq.) was added dropwise and the

resulting solution was stirred at −30 °C for 10 min. Then, 1 M HCl(aq) was added. The

two layers were separated and the aqueous layer was extracted with Et2O (3 x 10 mL).


pressure to give the crude product which contained a 86:14 mixture of alcohols syn-

(R,R)-273 and anti-(S,R)-273 by 1H NMR spectroscopy. Purification by flash column

chromatography on silica with 9:1-8:2 petrol-EtOAc as eluent gave alcohol anti-(S,R)-

273 (9 mg, 7%, 59:41 er by CSP-HPLC) as a white solid, CSP-HPLC: Chiracel AD-H


) (S,R)-273 7.4 min, (R,S)-273 10.1 min and alcohol

syn-(R,R)-273 (95 mg, 72%, 75:25 er by CSP-HPLC) as a white solid, CSP-HPLC:

Chiracel AD-H (95:5 Hexane-iPrOH, 1.0 mL min-1

) (R,R)-273 18.3 min, (S,S)-273 20.5

min.



268

A solution of stannane (S)-272 (50 mg, 0.16 mmol, 1.0 eq.) in Et2O (3 mL) was added

dropwise to a stirred solution of n-BuLi (0.07 mL of a 2.5 M solution in hexanes, 0.18

mmol, 1.1 eq.) and (−)-sparteine (42 μL, 0.18 mmol, 1.1 eq.) in Et2O (2 mL) at −78 °C

under Ar. The resulting solution was stirred at −78 °C for 5 min. Then, benzaldehyde

(19 μL, 0.19 mmol, 1.2 eq.) was added dropwise. The resulting solution was stirred at

−78 °C for 10 min and 1 M HCl(aq) (10 mL) was added. The two layers were separated

and the aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic

layers were dried (MgSO4) and evaporated under reduced pressure to give the crude

product which contained an 87:13 mixture of alcohols syn-(R,R)-273 and anti-(S,R)-273

by 1H NMR spectroscopy. Purification by flash column chromatography on silica with

9:1-8:2 petrol-EtOAc as eluent gave alcohol anti-(S,R)-273 (4 mg, 10%, 62:38 er by

CSP-HPLC) as a white solid, CSP-HPLC: Chiracel AD-H (95:5 Hexane-iPrOH, 1.0 mL

min-1

) (S,R)-273 7.6 min, (R,S)-273 10.3 min and alcohol syn-(R,R)-273 (37 mg, 88%,


iPrOH, 1.0 mL min-1

) (R,R)-273 18.7 min, (S,S)-273 20.8 min.





resulting solution was stirred at −100 °C for 30 min. Then, benzaldehyde (76 μL, 0.75

mmol, 1.5 eq.) was added dropwise and the resulting solution was stirred at −100 °C for

1 h. Then, 1 M HCl(aq) (10 mL) was added and the two layers were separated. The

aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic layers were

dried (MgSO4) and evaporated under reduced pressure to give the crude product which

contained a 87:13 mixture of alcohols syn-(R,R)-273 and anti-(S,R)-273 by 1H NMR

spectroscopy. Purification by flash column chromatography on silica with 9:1-8:2

petrol-EtOAc as eluent gave alcohol anti-(S,R)-273 (9 mg, 7%, 57:43 er by CSP-HPLC)

as a white solid, CSP-HPLC: Chiracel AD-H (95:5 Hexane-iPrOH, 1.0 mL min-1

) (S,R)-

273 7.4 min, (R,S)-273 10.0 min and alcohol syn-(R,R)-273 (87 mg, 66%, 77:23 er by


min-1

) (R,R)-273 18.4 min, (S,S)-273 20.8 min.



269

1-[(2S)-2-[(R)-Hydroxy(phenyl)methyl]azetidin-1-yl]-2,2-dimethylpropane-1-thione

anti-(R,S)-273 and 1-[(2S)-2-[(S)-hydroxy(phenyl)methyl]azetidin-1-yl]-2,2-

dimethylpropane-1-thione syn-(S,S)-273

N OH

PhH

N OH

PhH

syn-(S,S)-273anti-(R,S)-273

S S


1.2 eq.), N-thiopivaloyl azetidine 101 (79 mg, 0.5 mmol, 1.0 eq.), (+)-sparteine

surrogate 1 (116 mg, 0.6 mmol, 1.2 eq.) in Et2O (5 mL) and benzaldehyde (76 μL, 0.75

mmol, 1.5 eq.) gave the crude product which contained an 86:14 mixture of alcohols

syn-(S,S)-273 and anti-(R,S)-273 by 1H NMR spectroscopy. Purification by flash

column chromatography on silica with 9:1-8:2 petrol-EtOAc as eluent gave alcohol

anti-(R,S)-273 (9 mg, 7%, 54:46 er by CSP-HPLC) as a white solid, CSP-HPLC:


) (S,R)-273 7.5 min, (R,S)-273 10.2

min and alcohol syn-(R,R)-273 (91 mg, 70%, 54:46 er by CSP-HPLC) as a white solid,

CSP-HPLC: Chiracel AD-H (95:5 Hexane-iPrOH, 1.0 mL min-1

) (R,R)-273 18.2 min,

(S,S)-273 20.4 min.



1.2 eq.), N-thiopivaloyl azetidine 101 (79 mg, 0.5 mmol, 1.0 eq.), diamine (S,S)-42

(186 mg, 0.6 mmol, 1.2 eq.) in Et2O (5 mL) and benzaldehyde (76 μL, 0.75 mmol, 1.5

eq.) gave the crude product which contained a 77:23 mixture of alcohols syn-(S,S)-273

and anti-(R,S)-273 by 1H NMR spectroscopy. Purification by flash column

chromatography on silica with 9:1-8:2 petrol-EtOAc as eluent gave alcohol anti-(R,S)-

273 (26 mg, 20%, 65:35 er by CSP-HPLC) as a white solid, CSP-HPLC: Chiracel AD-

H (95:5 Hexane-iPrOH, 1.0 mL min-1

) (S,R)-273 7.5 min, (R,S)-273 10.2 min and

alcohol syn-(R,R)-273 (96 mg, 73%, 53:47 er by CSP-HPLC) as a white solid, CSP-


) (R,R)-273 18.7 min, (S,S)-

273 20.9 min.



270


to a stirred solution of N-thiopivaloyl azetidine 101 (79 mg, 0.5 mmol, 1.0 eq.), (+)-

sparteine surrogate 1 (116 mg, 0.6 mmol, 1.2 eq.) and benzaldehyde (76 μL, 0.75 mmol,

1.5 eq.) in Et2O (5 mL) at −78 °C under Ar. The resulting solution was stirred at −78

°C for 30 min. Then, 1 M HCl(aq) (10 mL) was added. The two layers were separated

and the aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic

layers were dried (MgSO4) and evaporated under reduced pressure to give the crude

product which contained a 76:24 mixture of alcohols syn-(S,S)-273 and anti-(R,S)-273


9:1-8:2 petrol-EtOAc as eluent gave alcohol anti-(R,S)-273 (0.5 mg, 0.5%, 56:44 er by


min-1

) (S,R)-273 7.5 min, (R,S)-273 10.2 min and alcohol syn-(R,R)-273 (2 mg, 1.5%,


iPrOH, 1.0 mL min-1

) (R,R)-273 18.3 min, (S,S)-273 20.3 min and recovered 273 (58

mg, 73%) as a pale yellow oil.


1-[2-[Hydroxy(phenyl)methyl]azetidin-1-yl]-2,2-dimethylpropane-1-thione anti-

rac-273 and 1-[(2-[hydroxy(phenyl)methyl]azetidin-1-yl]-2,2-dimethylpropane-1-

thione syn-rac-273

N OH

PhH

N OH

PhH

syn-rac-273ant i-rac-273

S S


to a stirred solution of N-thiopivaloyl azetidine 101 (40 mg, 0.25 mmol, 1.0 eq.) in Et2O

(5 mL) at −40 °C under Ar. The resulting solution was stirred at −40 °C for 30 min.

Then, benzaldehyde (38 μL, 0.38 mmol, 1.5 eq.) was added dropwise. The resulting

solution was stirred at −40 °C for 10 min and 1 M HCl(aq) (10 mL) was added. The two



give the crude product which contained a 62:38 mixture of alcohols syn-rac-273 and


271

anti-rac-273 by 1H NMR spectroscopy. Purification by flash column chromatography

on silica with 9:1-8:2 petrol-EtOAc gave alcohol anti-rac-273 (14 mg, 21%) as a white

solid and alcohol syn-rac-273 (27 mg, 42%) as a white solid.


s-BuLi (0.23 mL of a 1.3M solution in hexanes, 0.3 mmol, 1.2 eq.) was added to a

stirred solution of N-thiopivaloyl azetidine 101 (40 mg, 0.25 mmol, 1.0 eq.) in Et2O (5

mL) at −40 °C under Ar. The resulting solution was stirred at −40 °C for 30 min and

then cooled to −78 °C and stirred at −78 °C for 10 min. Then, (−)-sparteine (68 μL,

0.30 mmol, 1.2 eq.) was added at the resulting solution was stirred for 30 min.

Benzaldehyde (38 μL, 0.38 mmol, 1.5 eq.) was added dropwise. The resulting solution

was stirred for 10 min at −78 °C and 1 M HCl(aq) was added. The two layers were

separated and the aqueous layer was extracted with Et2O (3 x 10 mL). The combined

organic layers were dried (MgSO4) and evaporated under reduced pressure to give the

crude product which contained a 75:25 mixture of alcohols syn-rac-273 and anti-rac-

273 by 1H NMR spectroscopy. Purification by flash column chromatography on silica

with 9:1-8:2 petrol-EtOAc as eluent gave alcohol anti-rac-273 (12 mg, 19%) as a white

solid and alcohol syn-rac-273 (28 mg, 43%) as a white solid.



dropwise to a stirred solution of stannane (S)-272 (43 mg, 0.13 mmol, 1.0 eq., 68:32 er)

in THF (5 mL) at −78 °C under Ar. The resulting solution was stirred at −78 °C for 5

min. Then, benzaldehyde (16 μL, 0.16 mmol, 1.2 eq.) was added dropwise. The

resulting solution was stirred at −78 °C for 10 min and 1 M HCl(aq) (10 mL) was added.

The two layers were separated and the aqueous layer was extracted with Et2O (3 x 10

mL) and the combined layers were dried (MgSO4) and evaporated under reduced

pressure to give the crude product which contained a 75:25 mixture of alcohols syn-rac-

273 and anti-rac-273 by 1H NMR spectroscopy. Purification by flash column

chromatography on silica with 9:1-8:2 petrol-EtOAc as eluent gave alcohol anti-rac-

273 (9 mg, 26%, 50:50 er by CSP-HPLC) as a white solid, CSP-HPLC: Chiracel AD-H


) (S,R)-273 7.3 min, (R,S)-273 9.8 min and alcohol

syn-rac-273 (20 mg, 58%, 50:50 er by CSP-HPLC) as a white solid, CSP-HPLC:


272


) (R,R)-273 18.0 min, (S,S)-273 20.3

min.



dropwise to a stirred solution of stannane (S)-272 (43 mg, 0.13 mmol, 1.0 eq., 68:32 er)

and TMEDA (21 μL, 0.14 mmol, 1.1 eq.) in Et2O (5 mL) at −78 °C under Ar. The

resulting solution was stirred at −78 °C for 5 min. Then, benzaldehyde (16 μL, 0.16

mmol, 1.2 eq.) was added dropwise. The resulting solution was stirred at −78 °C for 10

min and 1 M HCl(aq) (10 mL) was added. The two layers were separated and the



contained a 76:24 mixture of alcohols syn-rac-273 and anti-rac-273 by 1H NMR


petrol-EtOAc as eluent gave alcohol anti-rac-273 (8 mg, 24%, 50:50 er by CSP-HPLC)

as a white solid CSP-HPLC: Chiracel AD-H (95:5 Hexane-iPrOH, 1.0 mL min-1

) (S,R)-

273 7.4 min, (R,S)-273 10.1 min and alcohol syn-rac-273 (21 mg, 61%, 50:50 er by


min-1

) (R,R)-273 18.5 min, (S,S)-273 20.4 min.

(S)-1-(tert-Butoxycarbonyl)azetidine-2-carboxylic acid (S)-285232

NBoc O

OHH

(S)-285

NaOH (420 mg, 10.5 mmol, 1.05 eq.) was added to a stirred solution of (S)-2-azetidine

carboxylic acid (1.00 g, 10.0 mmol, 1.0 eq.) and di-tert-butyl dicarbonate (2.83 g, 12.5

mmol, 1.25 eq.) in 2:1 EtOH-water (30 mL) at rt. The resulting solution was stirred at rt

for 16 h. Then, the volatiles were evaporated under reduced pressure and the remaining

suspension was acidified with 1 M HCl(aq) (20 mL). The aqueous layer was extracted

with EtOAc (3 x 50 mL). The combined organic layers were dried (MgSO4) and

evaporated under reduced pressure to give acid (S)-285 (1.96 g, 99%) as a white solid,

mp 97-99 °C (lit.,233

97-98 °C); 1

H NMR (400 MHz, CDCl3) δ 9.03 (br s, 1H, OH), 4.77


273

(br s, 1H, NCH), 3.96-3.85 (m, 2H, NCH2), 2.46 (br s, 2H, CH2), 1.46 (s, 9H, CMe3);

13C NMR (100.6 MHz, CDCl3) δ 181.5 (C=O, COOH), 156.6 (C=O, Boc), 82.7 (CMe3),

60.7 (br, NCH), 47.1 (NCH2), 28.2 (CMe3), 19.7 (CH2); [α]D −168.1 (c 0.7 in CHCl3)

(lit.,102

[α]D −116.1 (c 0.75 in CHCl3)). Spectroscopic data consistent with those



tert-Butyl 2S-benzoylazetidine-1-carboxylate (S)-286234

NBoc O

NHMe

OMe

NBoc O

PhH

(S)-286

N-Me morpholine (0.62 mL, 5.6 mmol, 1.2 eq.), HOBt (870 mg, 5.6 mmol, 1.2 eq.) and

EDC (0.98 mL, 5.6 mmol, 1.2 eq.) were added sequentially to a stirred solution of acid

(S)-285 (1.00 g, 4.6 mmol, 1.0 eq.) and N,O-dimethylhydroxylamine.HCl (550 mg, 5.6

mmol, 1.2 eq.) in DMF (10 mL) at 0 °C under Ar. The resulting solution was stirred at

0 °C for 2 h and then allowed to warm to rt and stirred at rt for 16 h. Then, EtOAc (30

mL) was added and the solution was washed with 1 M HCl(aq) (10 mL), 2 M NaOH(aq)

(2 x 10 mL) and brine (3 x 10 mL), dried (MgSO4) and evaporated under reduced

pressure to give the crude Weinreb amide (565 mg, 50%) as a pale yellow solid, 1H

NMR (400 MHz, CDCl3) δ 5.04 (dd, J = 8.5, 5.5 Hz, 1H, NCH), 4.04 (ddd, J = 9.0, 8.0,

6.0 Hz, 1H, NCHAHB), 3.87 (ddd, J = 9.0, 8.0, 6.0 Hz, 1H, NCHAHB), 3.71 (s, 3H,

OMe), 3.22 (s, 3H, NMe), 2.51-2.42 (m, 1H, CHAHB), 2.12 (ddt, J = 11.0, 9.0, 5.5 Hz,

1H, CHAHB), 1.43 (s, 9H, CMe3). PhMgCl (1.72 mL of a 2.0 M solution in THF, 3.44

mmol, 1.5 eq.) was added dropwise to a stirred solution of the crude Weinreb amide

(565 mg, 2.3 mmol, 1.0 eq.) in THF (10 mL) at −78 °C under Ar. The resulting solution

was stirred at −78 °C for 2 h. Then, saturated NH4Cl(aq) (15 mL) was added. The two

layers were separated and the aqueous layer was extracted with EtOAc (3 x 15 mL).



silica with 4:1-3:1 petrol-EtOAc as eluent gave ketone (S)-286 (430 mg, 36% over two

steps) as a white solid, mp 77-79 °C; RF (3:1 petrol-EtOAc) 0.3; IR (CHCl3) 2981, 1720

(C=O, PhCO), 1675 (C=O, Boc), 1426, 1375, 1210, 1010, 920, 815, 730 cm−1

; 1H NMR


274

(400 MHz, CDCl3) δ 7.85-7.83 (m, 2H, o-Ph), 7.52 (d, J = 7.5 Hz, 1H, p-Ph), 7.41 (t, J

= 7.5 Hz, 2H, m-Ph), 5.50 (dd, J = 9.5, 5.5 Hz, 1H, NCH), 3.99-3.87 (m, 2H, NCH2),

2.61 (dddd, J = 11.0, 9.5, 9.0, 6.0 Hz, 1H, CHAHB), 2.06 (ddt, J = 11.0, 9.0, 5.5 Hz, 1H,

CHAHB), 1.34 (s, 9H, CMe3); 13

C NMR (100.6 MHz, CDCl3) δ 195.7 (C=O, PhCO),

155.8 (C=O, Boc), 134.4 (ipso-Ph), 133.6 (Ph), 128.9 (Ph), 128.2 (Ph), 79.8 (CMe3),

63.6 (br, NCH), 46.9 (br, NCH2), 28.32 (CMe3), 21.3 (CH2); MS (ESI) m/z 284 [(M +

Na)+, 100]; HRMS m/z calcd for C15H19NO3 (M + Na)

+ 284.1257, found 284.1249 (+3.0

ppm error); [α]D −140.9 (c 0.65 in CHCl3).


tert-Butyl (2S)-2-[(S)-hydroxy(phenyl)methyl]azetidine-1-carboxylate syn-(S,S)-284

and tert-butyl (2S)-2-[(R)-hydroxy(phenyl)methyl]azetidine-1-carboxylate anti-

(R,S)-284

NBoc OH

PhH

NBoc OH

PhH

anti-(R,S)-284syn-(S,S)-284

NaBH4 (73 mg, 1.93 mmol, 1.2 eq.) was added to a stirred solution of ketone (S)-286

(420 mg, 1.61 mmol, 1.0 eq.) in MeOH (5 mL) at 0 °C. The resulting solution was

stirred at rt for 30 min. Then, the solution was cooled to 0 °C and saturated NH4Cl(aq) (5

mL) was added dropwise. The resulting solution was extracted with EtOAc (3 x 10

mL). The combined organic layers were dried (MgSO4) and evaporated under reduced

pressure to give the crude product which contained an 85:15 mixture of alcohols syn-

(S,S)-284 and anti-(R,S)-284 by 1H NMR spectroscopy. Purification by flash column

chromatography on silica with 9:1-8:2 petrol-EtOAc as eluent gave alcohol syn-(S,S)-

284 (330 mg, 78%, 99:1 er by CSP-HPLC) as a colourless oil, RF (4:1 petrol-EtOAc)

0.3; IR (CHCl3) 3348 (OH), 2976, 2952, 1687 (C=O), 1445, 1424, 1375, 1246, 1045,

1025, 915, 800, 730 cm−1

; 1H NMR (400 MHz, CDCl3) δ 7.29-7.36 (m, 2H, o-Ph), 7.34-

7.25 (m, 3H, Ph), 5.75 (br s, 1H, OH), 4.75 (d, J = 8.0 Hz, 1H, OCH), 4.34 (q, J = 8.0

Hz, 1H, NCH), 3.83-3.72 (m, 2H, NCH2), 1.93-1.80 (m, 2H, CH2), 1.48 (s, 9H, CMe3);

13C NMR (100.6 MHz, CDCl3) δ 158.1 (C=O), 139.2 (ipso-Ph), 128.3 (Ph), 127.9 (Ph),

127.0 (Ph), 80.1 (OCH), 79.1 (CMe3), 67.8 (NCH), 46.1 (NCH2), 28.3 (CMe3), 18.7

(CH2); MS (ESI) m/z 286 [(M + Na)+, 100], 264 [(M + H)

+, 50], 208 (100), 190 (90);


275

HRMS m/z calcd for C15H21NO3 (M + Na)+ 286.1414, found 286.1408 (+2.1 ppm

error); [α]D +1.0 (c 1.3 in CHCl3); CSP-HPLC: Chiracel AD-H (95:5 Hexane-iPrOH,

1.0 mL min-1

) (R,R)-284 11.1 min, (S,S)-284 24.0 min and alcohol anti-(R,S)-284 (65

mg, 15%, 99:1 er by CSP-HPLC) as a colourless oil, RF (4:1 petrol-EtOAc) 0.2; IR

(film) 3421 (OH), 2970, 1692 (C=O), 1446, 1420, 1378, 1186, 1050, 1040, 910, 730

cm−1

; 1H NMR (400 MHz, CDCl3) δ 7.29-7.36 (m, 2H, o-Ph), 7.34-7.25 (m, 3H, Ph),

5.75 (br s, 1H, OH), 4.94 (d, J = 2.5 Hz, 1H, OCH), 4.57 (td, J = 7.5, 2.5 Hz, 1H, NCH),

3.73 (dt, J = 8.5, 1.5 Hz, 1H, NCHAHB), 3.48-3.43 (m, 1H, NCHAHB), 2.16-2.04 (m,

1H, CHAHB), 1.93 (dddd, J = 11.5, 8.5, 7.5 5.0 Hz, 1H, CHAHB), 1.48 (s, 9H, CMe3);

13C NMR (100.6 MHz, CDCl3) δ 157.4 (C=O), 139.6 (ipso-Ph), 128.3 (Ph), 127.6 (Ph),

126.7 (Ph), 80.4 (CMe3), 75.3 (OCH), 66.8 (NCH), 46.7 (NCH2), 28.5 (CMe3), 16.2

(CH2); MS (ESI) m/z 286 [(M + Na)+, 100]; HRMS m/z calcd for C15H21NO3 (M + Na)

+

286.1414, found 286.1398 (+5.3 ppm error); [α]D −88.5 (c 1.05 in CHCl3); CSP-HPLC:


) (R,R)-284 11.3 min, (S,S)-284 25.7

min.


tert-Butyl (2R)-2-[(S)-hydroxy(phenyl)methyl]azetidine-1-carboxylate anti-(S,R)-

284

NBoc OH

PhH

ant i-(S,R)-284

MeLi (0.38 mL of a 1.6 M solution in Et2O, 0.60 mmol, 6.0 eq.) was added dropwise to

a stirred solution of alcohol anti-(S,R)-273 (26 mg, 0.25 mmol, 1.0 eq., 58:42 er) in

THF (5 mL) at 0 °C under Ar. The resulting solution was stirred at 0 °C for 5 h. Then,

1 M HCl(aq) (5 mL) was added dropwise. The resulting solution was extracted with

Et2O (10 mL). The aqueous layer was adjusted to pH 12 by dropwise addition of 1 M

NaOH(aq) and extracted with Et2O (3 x 10 mL). The combined organic layers were

dried (MgSO4) and evaporated under reduced pressure to give the crude amino alcohol.

The residue was dissolved in CH2Cl2 (5 mL) and di-tert-butyl dicarbonate (60 mg, 0.28

mmol, 1.1 eq.) was added at rt under Ar. The resulting solution was stirred at rt for 16

h. Then, 1 M HCl(aq) (10 mL) was added and the two layers were separated. The


276

aqueous layer was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers



eluent gave alcohol anti-(S,R)-284 (20 mg, 76%, 57:43 er by CSP HPLC) as a

colourless oil, [α]D +14.2 (c 0.60 in CHCl3); CSP-HPLC: Chiracel AD-H (95:5 Hexane-

iPrOH, 0.5 mL min-1

) (S,R)-284 14.9 min, (R,S)-284 15.8 min.


tert-Butyl (2R)-2-[(R)-hydroxy(phenyl)methyl]azetidine-1-carboxylate syn-(R,R)-

284

NBoc OH

PhH

syn-(R,R)-284


a stirred solution of alcohol syn-(R,R)-273 (65 mg, 0.25 mmol, 1.0 eq., 75:25 er.) in

THF (5 mL) at 0 °C under Ar. The resulting solution was stirred at 0 °C for 5 h. Then,







h. Then, 1 M HCl(aq) (10 mL) was added and the two layers were separated. The

aqueous layer was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers



eluent gave alcohol syn-(R,R)-284 (47 mg, 71%, 75:25 er by CSP HPLC) as a colourless

oil, [α]D −1.56 (c 1.1 in CHCl3); CSP-HPLC: Chiracel AD-H (95:5 Hexane-iPrOH, 1.0

mL min-1

) (R,R)-284 11.1 min, (S,S)-284 25.5 min.



277

(S)-2,2-dimethyl-1-(2-(trimethylstannyl)azetidin1-yl)propane-1-thione (S)-272

NSnMe3

H

S

(S)-272



(0.41 mL, 1.8 mmol, 1.2 eq.) in Et2O (8 mL) and Me3SnCl (2.25 mL of a 1.0 M in

hexane, 2.25 mmol, 1.5 eq.) gave the crude product. Purification by flash column

chromatography on silica with 95:5-9:1 petrol-Et2O as eluent gave stannane (S)-272

(263 mg, 55%, 68:32 er by CSP-HPLC) as a colourless oil, RF (9:1 petrol-Et2O) 0.3; 1

H

NMR (400 MHz, CDCl3) δ 4.65-4.47 (m, 3H, NCH), 2.57-2.48 (m, 1H, CH), 2.26-2.18

(m, 1H, CH), 1.33 (s, 9H, CMe3), 0.15 (s, 9H, SnMe3); 13


202.4 (C=S), 61.6 (NCH), 56.8 (NCH2), 42.4 (CMe3), 29.9 (CMe3), 18.3 (CH2), −7.7

(SnMe3); CSP-HPLC: Chiracel OD-H (99.5:0.5 Hexane-iPrOH, 1.0 mL min-1

) (S)-272

5.4 min, (R)-272 8.1 min. Spectroscopic data consistent with those reported in the

literature.102

The absolute configuration of the major enantiomer is assumed by analogy

with the benzaldehyde trapping.

Lab Book Reference 8/620 637 629

2,2-Dimethyl-1-(2-(trimethylstannyl)azetidin1-yl)propane-1-thione rac-272

NSnMe3

rac-272

S


1.2 eq.), N-thiopivaloyl azetidine 101 (236 mg, 1.5 mmol, 1.0 eq.) and TMEDA (0.27

mL, 1.8 mmol, 1.2 eq.) in Et2O (8 mL) and Me3SnCl (2.25 mL of a 1.0 M in hexane,


chromatography on silica with 95:5-9:1 petrol-Et2O as eluent gave stannane rac-272




278

(S)-2,2-Dimethyl-1-(2-methylazetidin-1-yl)propane-1-thione (S)-102

NMe

H

S

(S)-102



(0.14 mL, 0.60 mmol, 1.2 eq.) in Et2O (5 mL) and methyl iodide (47 μL, 0.75 mmol, 1.5

eq.) gave the crude product. Purification by flash column chromatography on silica with

9:1-8:2 petrol-Et2O as eluent gave methylated azetidine (S)-102 (79 mg, 91%, 59:41 er

by CSP-HPLC) as a colourless oil, RF (8:2 petrol-Et2O) 0.3; 1

H NMR (400 MHz,

CDCl3) δ 4.91-4.82 (m, 1H, NCH), 4.57 (dddd, J = 10.5, 9.0, 7.0, 1.5 Hz, 1H,

NCHAHB), 4.43 (dddd, J = 10.5, 10.0, 5.0, Hz, 1H, NCHAHB), 2.54 (dddd, J = 11.0,

10.0, 9.0, 7.0 Hz, 1H, CHAHB), 1.85 (ddt, J = 11.0, 9.5, 5.0 Hz, 1H, NCHAHB), 1.62 (d,

J = 6.0 Hz, 3H, Me), 1.34 (s, 9H, CMe3); 13

C NMR (100.6 MHz, CDCl3) rotamers δ

209.6 (C=S), 65.7 (NCH), 64.8 (NCH), 55.6 (NCH2), 53.7 (NCH2), 43.2 (CMe3), 30.85

(CMe3), 29.6 (CMe3), 23.1 (CH2), 18.5 (Me); [α]D +0.2 (c 1.0 in CHCl3) (lit.,102

[α]D

−21.3 (c 1.15 in CHCl3 for (R)-102 of 99:1 er)); CSP-HPLC: Chiracel OD-H (99.9:0.1


) (R)-102 11.1 min, (S)-102 11.9 min. Spectroscopic data




to a stirred solution of N-thiopivaloyl azetidine 101 (79 mg, 0.5 mmol, 1.0 eq.) and (−)-


resulting solution was stirred at −78 °C for 30 min. Methyl iodide (47 μL, 0.75 mmol,

1.5 eq.) was added dropwise and the resulting solution was stirred at −78 °C for 2 h.

Then, benzaldehyde (76 μL, 0.75 mmol, 1.5 eq.) was added. The resulting solution was

stirred at −78 °C for 1 h and 1 M HCl(aq) was added. The two layers were separated and

the aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic layers




279

eluent gave methylated azetidine (S)-102 (67 mg, 78%, 58:42 er by CSP-HPLC) as a

colourless oil, CSP-HPLC: Chiracel OD-H (99.9:0.1 Hexane-iPrOH, 1.0 mL min-1

) (R)-

102 11.0 min, (S)-102 12.0 min.


(R)-2,2-Dimethyl-1-(2-methylazetidin-1-yl)propane-1-thione (R)-102

NMe

H

S

(R)-102

Using general procedure L, s-BuLi (0.46 mL of a 1.3M solution in hexanes, 0.60 mmol,

1.2 eq.), N-thiopivaloyl azetidine 101 (79 mg, 0.50 mmol, 1.0 eq.) and diamine (S,S)-42

(186 mg, 0.60 mmol, 1.2 eq.) in Et2O (5 mL) and methyl iodide (47 μL, 0.75 mmol, 1.5

eq.) gave the crude product. Purification by flash column chromatography on silica with

9:1-8:2 petrol-Et2O gave methylated azetidine (R)-102 (76 mg, 88%, 69:31 er by CSP-

HPLC) as a colourless oil, [α]D −2.0 (c 0.95 in CHCl3) (lit.,102

[α]D −21.3 (c 1.15 in

CHCl3 for (R)-102 of 99:1 er)); CSP-HPLC: Chiracel OD-H (99.9:0.1 Hexane-iPrOH,

1.0 mL min-1

) (R)-102 14.0 min, (S)-102 15.4 min.




eq.) and diamine (S,S)-42 (186 mg, 0.60 mmol, 1.2 eq.) in Et2O (5 mL) at −78 °C under

Ar. The resulting solution was stirred at −78 °C for 30 min. Then, a solution of methyl

iodide (31 μL, 0.50 mmol, 1.0 eq.) in Et2O (5 mL) was added dropwise via syringe

pump over 2 h. The resulting solution was stirred for 10 min at −78 °C and 1 M HCl(aq)

(10 mL) was added. The two layers were separated and the aqueous layer was extracted

with Et2O (3 x 10 mL). The combined organic layers were dried (MgSO4) and


column chromatography on silica with 9:1-8:2 petrol-Et2O as eluent gave methylated

azetidine (R)-102 (78 mg, 91%, 68:32 er by CSP-HPLC) as a colourless oil, CSP-


280

HPLC: Chiracel OD-H (99.9:0.1 Hexane-iPrOH, 1.0 mL min-1

) (R)-102 13.9 min, (S)-

102 15.4 min.


(S)-tert-Butyl 2-(hydroxymethyl)azetidine-1-carboxylate (S)-293

NBoc

H

(S)-293

OH

Borane dimethyl sulfide complex (0.51 mL, 5.42 mmol, 1.3 eq.) was added dropwise to

a stirred solution of N-Boc acid (S)-285 (840 mg, 4.17 mmol, 1.0 eq.) in THF (10 mL)

at 0 °C under Ar. After gas evolution ceased, the resulting solution was stirred and

heated at 66 °C for 1 h. Then, the solution was cooled to rt and MeOH (5 mL) was

added dropwise. The solvent was evaporated under reduced pressure to give the crude

product. Purification by flash column chromatography on silica with 6:4-1:1 petrol-

EtOAc as eluent gave alcohol (S)-293 (725 mg, 93%) as a colourless oil, RF (1:1 petrol-

EtOAc) 0.2; 1H NMR (400 MHz, CDCl3) δ 4.42 (br s, 1H, NCH), 4.25 (br s, 1H, OH),

3.88-3.82 (m, 1H, NCHAHB), 3.79-3.68 (m, 3H, NCHAHB + OCH2), 2.16 (tdd, J = 11.5,

9.0, 5.0 Hz, 1H, CHAHB), 1.91 (br s, 1H, CHAHB), 1.43 (s, 9H, CMe3); 13

C NMR

(100.6 MHz, CDCl3) δ 157.5 (C=O), 80.3 (CMe3), 67.0 (OCH2), 63.7 (NCH), 46.7

(NCH2), 28.3 (CMe3), 17.9 (CH2); [α]D −19.8 (c 0.45 in CHCl3) (lit.,102

[α]D −21.5 (c

0.83 in CHCl3)). Spectroscopic data consistent with those reported in the literature.102


(S)-tert-Butyl 2-(iodomethyl)azetidine-1-carboxylate (S)-294235

NBoc

H

(S)-294

I

Iodine (1.28 g, 5.06 mmol, 1.5 eq.) was added in three portions to a stirred solution of

imidazole (459 mg, 6.74 mmol, 2.0 eq.) and triphenylphosphine (1.33 g, 5.06 mmol, 1.5

eq.) in CH2Cl2 (15 mL) at 0 °C over 30 min. The resulting solution was allowed to

warm to rt and then stirred at rt for 10 min. Then, a solution of alcohol (S)-293 (630


281

mg, 4.17 mmol, 1.0 eq.) in CH2Cl2 (5 mL) was added dropwise and the resulting

solution was stirred at rt for 16 h. The solids were removed by filtration and the filtrate

was evaporated under reduced pressure. The residue was dissolved in Et2O (25 mL)

and the solids were removed by filtration. The organic layer was washed with sat.

Na2S2O3(aq) (15 mL), dried (MgSO4) and evaporated under reduced pressure to give the


EtOAc as eluent gave iodide (S)-294 (851 mg, 85%) as a colourless oil, RF (9:1 petrol-

EtOAc) 0.4; IR (CHCl3) 2975, 2968, 1695 (C=O), 1510, 1446, 1420, 1278, 1190, 1035,

915, 815, 731 cm−1

; 1H NMR (400 MHz, CDCl3) δ 4.21-4.15 (m, 1H, NCH), 3.81-3.69

(m, 2H, NCH), 3.51 (br d, J = 9.0 Hz, 1H, CHAHBI), 3.37 (t, 9.0 Hz, CHAHBI), 2.29

(dddd, J = 11.5, 9.0, 8.0, 5.5 Hz, 1H, CHAHB), 1.89 (dddd, J = 11.5, 9.0, 6.5, 6.0 Hz,

1H, CHAHB), 1.43 (s, 9H, CMe3); 13

C NMR (100.6 MHz, CDCl3) δ 155.6 (C=O), 79.7

(CMe3), 61.1 (NCH), 44.9 (NCH2), 28.3 (CMe3), 23.4 (CH2), 11.6 (CH2I); MS (ESI)

m/z 320 [(M + Na)+, 60], 241 (100); HRMS m/z calcd for C9H16INO2 (M + Na)

+

320.0118, found 320.0108 (+3.0 ppm error); [α]D −88.7 (c 0.95 in CHCl3).


(R)-tert-Butyl-2-methylazetidine-1-carboxylate (R)-292236

NBoc

H

(R)-292

5% Pd/C (65 mg, 10 wt% of (S)-294) was added to a stirred solution of iodide (S)-294

(650 mg, 2.18 mmol, 1.0 eq.) and Et3N (0.30 mL, 2.18 mmol, 1.0 eq.) in MeOH (10

mL) at rt. Then, the reaction flask evacuated under reduced pressure and back-filled

with Ar three times. After a final evacuation, a balloon of H2 was attached and the

reaction mixture was stirred vigorously at rt under H2 for 16 h. The solids were

removed by filtration through Celite®

and washed with CH2Cl2 (15 mL). Then, the

filtrate was evaporated under reduced pressure and the residue was dissolved in CH2Cl2

(15 mL) and washed with 1 M HCl(aq) (10 mL), dried (MgSO4) and evaporated under


chromatography on silica with 4:1 petrol-Et2O as eluent gave methyl azetidine (R)-292

(280 mg, 75%) as a colourless oil, RF (4:1 petrol-Et2O) 0.3; 1



282

δ 4.26 (pent, J = 6.5 Hz 1H, NCH), 3.81-3.77 (m, 2H, NCH2), 2.30-2.21 (m, 1H,

CHAHB), 1.74 (dtd, J = 11.0, 8.0, 6.0 Hz, 1H, CHAHB), 1.42 (s, 9H, CMe3), 1.35 (d, J =

6.5 Hz, Me); 13

C NMR (100.6 MHz, CDCl3) δ 156.4 (C=O), 78.9 (CMe3), 57.9 (br,

NCH), 45.7 (br, NCH2), 28.4 (CMe3), 23.6 (CH2), 21.5 (Me); [α]D −38.1 (c 1.0 in

CHCl3) (lit.,102

[α]D −40.5 (c 0.80 in CHCl3)). Spectroscopic data consistent with those



2,2-Dimethyl-1-pyrrolidin-1-ylpropan-1-thione 210102

N

210

S

Phosphorous(V) sulfide (17.78 g, 80.0 mmol, 1.25 eq.) was added to a stirred solution

amide 209 (10.0 g, 64 mmol, 1.0 eq.) in pyridine (100 mL) at rt under Ar. The resulting

solution was heated at 75 °C for 6 h. The solution was allowed to cool to rt and then

poured into 1 M HCl(aq) (150 mL). 1 M HCl(aq) was added until pH 3 was obtained. The

resulting solution was stirred at rt for 2 h and then extracted with CH2Cl2 (3 × 100 mL).

The combined organic extracts were washed with 1 M HCl(aq) (100 mL), water (100

mL) and brine (100 mL), dried (Na2SO4) and evaporated under reduced pressure to give


petrol-EtOAc as eluent gave thioamide 210 (5.09 g, 100%) as pale yellow needles, mp

32-35 °C (lit.,237

33-35 °C); RF (7:3 petrol-EtOAc) 0.5; 1H NMR (400 MHz, CDCl3) δ

3.83 (t, J = 7.0 Hz, 2H, NCH2), 3.74 (t, J = 7.0 Hz, 2H, NCH2), 1.95 (quintet, J = 7.0

Hz, 2H, CH2), 1.81 (quintet, J = 7.0 Hz, 2H, CH2), 1.29 (s, 9H, CMe3); 13

C NMR (100.6

MHz, CDCl3) rotamers δ 208.4 (C=S), 57.5 (NCH2), 52.7 (NCH2) 43.4 (CMe3), 30.1

(CMe3), 27.2 (CH2), 22.8 (CH2). Spectroscopic data consistent with those reported in

the literature.237



283

1-((R)-2-((S)-Hydroxy(phenyl)methyl)pyrrolidin-1-yl)-2,2-dimethylpropane-1-

thione anti-(S,R)-211 and 1-((R)-2-((R)-hydroxy(phenyl)methyl)pyrrolidin-1-yl)-

2,2-dimethylpropane-1-thione syn-(R,R)-211

N

S

Ph

OH

H

N

S

Ph

OH

H

ant i-(S,R)-211 syn-(R,R)-211


mmol, 1.3 eq.), (−)-sparteine (145 μL, 0.65 mmol, 1.3 eq.) and N-thiopivaloyl

pyrrolidine 210 (86 mg, 0.50 mmol, 1.0 eq.) in Et2O (5 mL) and benzaldehyde (76 μL,

0.75 mmol, 1.5 eq.) gave the crude product which contained a 58:42 mixture of

diastereomeric alcohols anti-(S,R)-211 and syn-(R,R)-211 by 1H NMR spectroscopy.


eluent gave alcohol anti-(S,R)-211 (55 mg, 40%, 86:14 er by CSP-HPLC) as a white

solid, mp 169-174 °C; RF (7:3 petrol-Et2O) 0.2; IR (CHCl3) 3386 (OH), 2972, 2876,

1604, 1478, 1411, 1383, 1365, 1160, 732 cm-1

; 1

H NMR (400 MHz, CDCl3) δ 7.53 (d,

J = 7.0 Hz, 2H, o-Ph), 7.34 (t, J = 7.0 Hz, 2H, m-Ph), 7.26 (t, J = 7.0 Hz, 1H, p-Ph),

5.90 (br s, 1H, OCH), 5.36-5.32 (m, 1H, NCH), 4.27-4.22 (m, 1H, NCHAHB), 3.52 (td,

, J = 11.0, 6.0 Hz, 1H, NCHAHB), 2.28 (br s, 1H, OH), 2.12-1.97 (m, 2H, CH), 1.75-

1.64 (m, 2H, CH), 1.44 (s, 9H, CMe3); 13

C NMR (100.6 MHz, CDCl3) δ 210.1 (C=S),

141.9 (ipso-Ph), 128.1 (Ph), 127.2 (Ph), 125.5 (Ph), 71.4 (OCH or NCH), 70.4 (OCH or

NCH), 54.7 (NCH2), 44.2 (CMe3), 30.7 (CMe3), 25.0 (CH2), 22.4 (CH2); MS (ESI) m/z

300 [(M + Na)+, 20], 278 [(M + H)

+, 100], 260 (30), 125 (40); HRMS m/z calcd for

C16H23NOS (M + H)+ 278.1573, found 278.1579 (−2.0 ppm error); [α]D −7.0 (c 1.0 in

CHCl3); CSP-HPLC: Chiracel AD (95:5 Hexane-iPrOH, 1.0 mL min-1

) (S,R)-211 11.3

min, (R,S)-211 14.7 min and alcohol syn-(R,R)-211 (50 mg, 37%, 82:18 er by CSP-

HPLC) as a colourless oil, RF (7:3 petrol-Et2O) 0.1; IR (film) 3387 (OH), 2973, 2876,

1605, 1452, 1411, 1383, 1365, 1162, 732 cm-1

; 1

H NMR (400 MHz, CDCl3) δ 7.41-7.29

(m, 5H, Ph), 5.68 (td, J = 8.0, 3.5 Hz, 1H, NCH), 5.29-5.26 (m, 1H, OCH), 4.11 (dt, J =

11.5, 5.5 Hz, 1H, NCHAHB), 3.97 (br d, J = 5.0 Hz, 1H, OH), 3.25-3.18 (m, 1H,

NCHAHB), 1.90-1.73 (m, 4H, CH), 1.45 (s, 9H, CMe3); 13

C NMR rotamers (100.6 MHz,

CDCl3) δ 212.6 (C=S), 141.8 (ipso-Ph), 128.3 (Ph), 128.5 (Ph), 128.3 (Ph), 127.8 (Ph),


284

127.6 (Ph), 127.1 (Ph), 127.0 (Ph), 74.4 (br, OCH), 69.8 (NCH), 65.3 (NCH2), 52.7

(NCH2), 44.3 (CMe3), 30.7 (CMe3), 24.3 (CH2), 24.1 (CH2); MS (ESI) m/z 300 [(M +

Na)+, 20], 278 [(M + H)

+, 100], 260 (20), 125 (20); HRMS m/z calcd for C16H23NOS (M

+ H)+ 278.1573, found 278.1570 (1.1 ppm error); [α]D +94.2 (c 0.8 in CHCl3); CSP-

HPLC: Chiracel AD (90:10 Hexane-iPrOH, 1.0 mL min-1

) (R,R)-211 10.6 min, (S,S)-

211 22.4 min.

Lab Book Reference PJR 8/636 6/501

A solution of stannane rac-297 (100 mg, 0.30 mmol, 1.0 eq.) in Et2O (3 mL) was added

to a stirred solution of n-BuLi (0.13 mL of a 2.5 M solution in hexane, 0.33 mmol, 1.1

eq.) and (−)-sparteine (77 μL, 0.33 mmol, 1.1 eq.) in Et2O (2 mL) at −78 °C under Ar.

The resulting solution was stirred at −78 °C for 5 min. Then, benzaldehyde (46 μL,

0.45 mmol, 1.5 eq.) was added dropwise. The resulting solution was stirred at −78 °C

for 1 h and 1 M HCl(aq) (10 mL) was added. The two layers were separated and the



contained a 55:45 mixture of diastereomeric alcohols anti-(S,R)-211 and syn-(R,R)-211


8:2-7:3 petrol-Et2O as eluent gave alcohol anti-(S,R)-211 (32 mg, 39%, 88:12 er by

CSP-HPLC) as a white solid, CSP-HPLC: Chiracel AD (95:5 Hexane-iPrOH, 1.0 mL

min-1

) (S,R)-211 11.7 min, (R,S)-211 15.2 min and alcohol syn-(R,R)-211 (29 mg, 35%,

82:18 er by CSP-HPLC) as a colourless oil, CSP-HPLC: Chiracel AD (90:10 Hexane-

iPrOH, 1.0 mL min-1

) (R,R)-211 9.8 min, (S,S)-211 18.8 min.


1-((S)-2-((R)-Hydroxy(phenyl)methyl)pyrrolidin-1-yl)-2,2-dimethylpropane-1-

thione anti-(R,S)-211 and 1-((S)-2-((S)-hydroxy(phenyl)methyl)pyrrolidin-1-yl)-2,2-

dimethylpropane-1-thione syn-(S,S)-211

N

S

Ph

OH

H

N

S

Ph

OH

H

ant i-(R,S)-211 syn-(S,S)-211


285


mmol, 1.3 eq.), (+)-sparteine surrogate 1 (120 mg, 0.65 mmol, 1.3 eq.) and N-

thiopivaloyl pyrrolidine 210 (86 mg, 0.50 mmol, 1.0 eq.) in Et2O (5 mL) and

benzaldehyde (76 μL, 0.75 mmol, 1.5 eq.) gave the crude product which contained a

78:22 mixture of diastereomeric alcohols anti-(R,S)-211 and syn-(S,S)-211 by 1H NMR


petrol-Et2O as eluent gave alcohol anti-(R,S)-211 (86 mg, 62%, 85:15 er by CSP-

HPLC) as a white solid, CSP-HPLC: Chiracel AD (95:5 Hexane-iPrOH, 1.0 mL min-1

)

(S,R)-211 11.2 min, (R,S)-211 14.6 min and alcohol syn-(S,S)-211 (33 mg, 24%, 92:8 er

by CSP-HPLC) as a colourless oil, CSP-HPLC: Chiracel AD (90:10 Hexane-iPrOH, 1.0

mL min-1

) (R,R)-211 10.8 min, (S,S)-211 19.8 min.


1-(2-(Hydroxy(phenyl)methyl)pyrrolidin-1-yl)-2,2-dimethylpropane-1-thione anti-

rac-211 and 1-(2-(hydroxy(phenyl)methyl)pyrrolidin-1-yl)-2,2-dimethylpropane-1-

thione syn-rac-211

N

S

Ph

OH

H

N

S

Ph

OH

H

ant i-rac-211 syn-rac-211

n-BuLi (26 μL of a 2.5M solution in hexanes, 0.066 mmol, 1.1 eq.) was added to a

stirred solution of stannane (S)-297 (20 mg, 0.06 mmol, 1.0 eq., 78:22 er) in THF (5


benzaldehyde (7 μL, 0.07 mmol, 1.2 eq.) was added dropwise. The resulting solution

was stirred at −78 °C for 10 min and 1 M HCl(aq) (10 mL) was added. The two layers

were separated and the aqueous layer was extracted with Et2O (3 x 10 mL). The


give the crude product which contained a 60:40 mixture of alcohols syn-rac-211 and

anti-rac-211 by 1H NMR spectroscopy. Purification by flash column chromatography

on silica with 9:1-8:2 petrol-EtOAc as eluent gave alcohol anti-rac-211 (7 mg, 42%,

51:49 er by CSP-HPLC) as a white solid, CSP-HPLC: Chiracel AD (95:5 Hexane-

iPrOH, 1.0 mL min-1

) (S,R)-211 11.2 min, (R,S)-211 14.6 min and alcohol syn-rac-211


286

(9 mg, 52%, 51:49 er by CSP-HPLC) as a white solid, CSP-HPLC: Chiracel AD (90:10


) (R,R)-211 10.6 min, (S,S)-211 23.1 min.


n-BuLi (26 μL of a 2.5M solution in hexanes, 0.066 mmol, 1.1 eq.) was added to a

stirred solution of stannane (S)-297 (20 mg, 0.06 mmol, 1.0 eq., 78:22 er) and TMEDA

(10 μL, 0.066 mmol, 1.1 eq.) in Et2O (5 mL) at −78 °C under Ar. The resulting solution

was stirred at −78 °C for 5 min. Then, benzaldehyde (7 μL, 0.07 mmol, 1.2 eq.) was

added dropwise. The resulting solution was stirred at −78 °C for 10 min and 1 M

HCl(aq) (10 mL) was added. The two layers were separated and the aqueous layer was

extracted with Et2O (3 x 10 mL). The combined layers were dried (MgSO4) and

evaporated under reduced pressure to give the crude product which contained a 76:24

mixture of alcohols syn-rac-211 and anti-rac-211 by 1H NMR spectroscopy.


eluent gave alcohol anti-rac-211 (8 mg, 24%, 50:50 er by CSP-HPLC) as a white solid,

CSP-HPLC: Chiracel AD (95:5 Hexane-iPrOH, 1.0 mL min-1

) (S,R)-211 11.3 min,

(R,S)-211 14.7 min and alcohol syn-rac-211 (21 mg, 61%, 50:50 er by CSP-HPLC) as a

white solid, CSP-HPLC: Chiracel AD (90:10 Hexane-iPrOH, 1.0 mL min-1

) (R,R)-211

10.6 min, (S,S)-211 23.0 min.


tert-Butyl (2R)-2-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate syn-(R,R)-

73

syn-(R,R)-73

NBoc

H

Ph

OH


a stirred solution of alcohol syn-(R,R)-211 (43 mg, 0.16 mmol, 1.0 eq., 82:18 er) in THF

(5 mL) at 0 °C under Ar. The resulting solution was stirred at 0°C for 5 h. Then, 1 M

HCl(aq) (5 mL) was added dropwise. The resulting solution was extracted with Et2O

(10 mL). The aqueous layer was adjusted to pH 12 by dropwise addition of 1 M



287




h. Then, 1 M HCl(aq) (10 mL) was added and the two layers separated. The aqueous

layer was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were dried

(MgSO4) and evaporated under reduced pressure to give the crude product. Purification

by flash column chromatography on silica with 98:2 CH2Cl2-acetone as eluent gave

alcohol syn-(R,R)-73 (30 mg, 70%, 82:18 er by CSP HPLC) as a colourless oil, [α]D

−0.6 (c 0.75 in CHCl3) (lit.,74

[α]D −1.6 (c 1.0 in CHCl3 for (R,R)-73 of 97:3 er)); CSP-

HPLC: Chiracel OD (98:2 Hexane-iPrOH, 0.5 mL min-1

) (R,R)-73 28.6 min, (S,S)-73

35.7 min. Spectroscopic data consistent with those reported in the literature.74


tert-Butyl (2R)-2-[(S)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate anti-(S,R)-

73

syn-(S,R)-73

NBoc

H

Ph

OH


a stirred solution of alcohol anti-(S,R)-211 (33 mg of 86:14 er, 0.12 mmol, 1.0 eq.) in

THF (5 mL) at 0 °C under Ar. The resulting solution was stirred at 0°C for 5 h. Then,







h. Then, 1 M HCl(aq) (10 mL) was added and the two layers separated. The aqueous

layer was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were dried

(MgSO4) and evaporated under reduced pressure to give the crude product. Purification

by flash column chromatography on silica with 98:2 CH2Cl2-acetone as eluent gave

alcohol anti-(S,R)-73 (17 mg, 50%, 86:14 er by CSP HPLC) as a colourless oil, [α]D


288

+79.4 (c 1.0 in CHCl3) (lit.,74

[α]D +112.7 (c 1.5 in CHCl3 for (S,R)-73 of 96:4 er));

CSP-HPLC: Chiracel OD (99:1 Hexane-iPrOH, 0.5 mL min-1

) (S,R)-73 25.7 min, (R,S)-

73 28.3 min. Spectroscopic data consistent with those reported in the literature.74


(S)-2,2-Dimethyl-1-(2-(trimethylstannyl)pyrrolidin-1-yl)propane-1-thione (S)-297

N

S

SnMe3

H

(S)-297

Using general procedure M, s-BuLi (1.0 mL of a 1.3 M solution in hexanes, 1.30 mmol,

1.3 eq.), N-thiopivaloyl pyrrolidine 210 (171 mg, 1.00 mmol, 1.0 eq.) and (−)-sparteine

(296 μL, 1.30 mmol, 1.3 eq.) in Et2O (7 mL) and trimethyltin chloride (1.50 mL of a 1.0

M solution in hexanes, 1.5 mmol, 1.5 eq.) gave the crude product. Purification by flash

column chromatography on silica with 95:5 petrol-EtOAc as eluent gave stannane (S)-

297 (228 mg, 68%, 78:22 er by CSP-HPLC) as a colourless oil, RF (95:5 petrol-EtOAc)

0.3; IR (film) 2978, 1500, 1482, 1448, 1390, 1370, 1246, 1074, 1036, 912, 809, 730

cm−1

; 1H NMR (400 MHz, CDCl3) δ 4.37-4.28 (m, 1H, NCH), 3.91-3.78 (m, 2H,

NCH2), 2.20-2.09 (m, 2H, CH2), 2.07-2.01 (m, 1H, CH), 1.98-1.88 (m, 1H, CH), 1.40

(s, 9H, CMe3), 0.07 (s, 9H, SnMe3); 13

C NMR (100.6 MHz, CDCl3) δ 201.0 (C=S), 63.7

(NCH), 53.1 (NCH2), 43.1 (CMe3), 30.7 (CMe3), 28.2 (CH2), 27.6 (CH2), −6.7 (SnMe3);

MS (ESI) m/z 336 [(M(120

Sn) + H)+, 100], 334 [(M(

118Sn) + H)

+, 70], 332 [(M(

116Sn) +

H)+, 30]; HRMS m/z calcd for C12H25NS

120Sn (M + Na)

+ 336.0803 (−1.0 ppm error),

found 336.0806; [α]D +290.89 (c 0.70 in CHCl3); CSP-HPLC: Chiracel OD-H (99.5:0.5


) (S)-297 4.9 min, (R)-297 6.4 min. The absolute

configuration of the major enantiomer is assumed by analogy to benzaldehyde-

trappings.



289

(S)-2,2-Dimethyl-1-(2-(trimethylstannyl)pyrrolidin-1-yl)propane-1-thione rac-297

N

S

SnMe3

rac-297

Using general procedure M, s-BuLi (1.0 mL of a 1.3 M solution in hexanes, 1.30 mmol,

1.3 eq.), N-thiopivaloyl pyrrolidine 210 (171 mg, 1.00 mmol, 1.0 eq.) and TMEDA (194

μL, 1.30 mmol, 1.3 eq.) in Et2O (7 mL) and trimethyltin chloride (1.50 mL of a 1.0 M

solution in hexanes, 1.5 mmol, 1.5 eq.) gave the crude product. Purification by flash

column chromatography on silica with 95:5 petrol-EtOAc as eluent gave stannane rac-

297 (254 mg, 76%) as a colourless oil.


(S)-2,2-dimethyl-1-(2-methylpyrrolidin-1-yl)propane-1-thione (S)-298

N

S

Me

(S)-298

H


mmol, 1.3 eq.), N-thiopivaloyl pyrrolidine 210 (86 mg, 0.50 mmol, 1.0 eq.) and (−)-

sparteine (0.15 mL, 0.65 mmol, 1.3 eq.) in Et2O (5 mL) and methyl iodide (47 μL, 0.75

mmol, 1.5 eq.) gave the crude product. Purification by flash column chromatography

on silica with 9:1-8:2 petrol-Et2O as eluent gave methylated pyrrolidine (S)-298 (78 mg,

84%, 58:42 er by CSP-HPLC) as a colourless oil. RF (8:2 petrol-Et2O) 0.3; IR (film)

2975, 2876, 1530, 1458, 1410, 1325, 1116, 730 cm-1

; 1H NMR (400 MHz, CDCl3)

85:15 mixture of rotamers δ 5.15-5.07 (m, 0.85H, NCH), 4.84-4.78 (m, 0.15H, NCH),

4.21 (dt, J = 14.5, 8.5 Hz, 0.15H, NCHAHB), 4.00 (ddd, J = 13.5, 12.0, 7.0 Hz, 0.85H,

NCHAHB), 3.83-3.76 (m, 0.15H, NCHAHB), 3.67 (dt, J = 13.5, 6.5 Hz, 0.85H,

NCHAHB), 2.13-1.86 (m, 3H, CH), 1.66-1.59 (m, 1H, CH), 1.43 (s, 1.35H, CMe3), 1.39

(s, 7.65H, CMe3), 1.33 (d, J = 6.5 Hz, 2.55H, Me), 1.24 (d, J = 6.0 Hz, 0.45H, Me); 13

C

NMR (100.6 MHz, CDCl3) δ 208.8 (C=S), 61.8 (NCH), 52.0 (NCH2), 44.0 (CMe3),

30.6 (CMe3), 30.4 (CH2), 24.9 (CH2), 17.7 (Me); MS (ESI) m/z 208 [(M + Na)+, 100],


290

186 [(M + H)+, 20]; HRMS m/z calcd for C10H19NS (M + Na)

+ 208.1136, found

208.1131 (−0.5 ppm error); [α]D −10.1 (c 0.95 in CHCl3); CSP-HPLC: Chiracel OD-H

(99.5:0.5 Hexane-iPrOH, 1.0 mL min-1

) (S)-298 8.0 min, (R)-298 9.0 min. The absolute

configuration of the major enantiomer was assigned by comparison to unpublished

results within our group (conversion of (S)-298 into known compound).212


Chapter Six: Abbreviations

291


Ac Acetyl

aq. Aqueous

Bn Benzyl

Boc t-butoxycarbonyl

bp Boiling Point

br Broad

Bu Butyl

Cb N,N-Diisoproylcarbamoyl

CIPE Complex induced proximity effect

cm-1

Wavenumber

CSP-HPLC Chiral Stationary Phase High Performance Liquid Chromatography

δ Chemical shift

d Doublet

DET Diethyl tartrate

DMAP 4-Dimethylaminopyridine

DMF Dimethylformamide

dr Diastereomeric ratio

E+

Electrophile

EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

ESI Electrospray ionisation

eq. Equivalent(s)

er Enantiomeric ratio

g Gram(s)

GC Gas chromatography

h Hour(s)

HFIP Hexafluoroisopropanol


292

HOBt Hydroxybenzotriazole

HRMS High resolution mass spectrometry

Hz Hertz

i-Pr Isopropyl

IR Infra-red

J Coupling constant in Hz

KHMDS Potassium hexamethyldisilazide

LHMDS Lithium hexamethyldisilazide

M Molar

M+ Molecular ion

m Multiplet

mCPBA meta-Chloroperoxybenzoic acid

Me Methyl

mg Milligrams

min Minutes

mL Millilitre

mmol Millimole

mol Mole

MOM Methoxymethyl ether

mp. Melting Point

MS Mass Spectrometry

MTBE Methyl tert-butyl ether

m/z Mass to charge ratio

NCS N-Chlorosuccinimide

NMR Nuclear Magnetic Resonance

Ns 4-Nitrobenzenesulfonyl

Petrol Petroleum ether (Fraction which boils at 40-60 °C)

Ph Phenyl


293

PMP para-Methoxyphenyl

ppm Parts per million

PPTS Pyridinium p-toluenesulfonate

q Quartet

R Alkyl group

RSM Recovered starting material

RF Retention factor

rt Room temperature

s Singlet

SEM [2-(Trimethysilyl)ethoxy]methyl

sp. Sparteine

(+)-sp. surr. (+)-Sparteine surrogate

s-Bu s-Butyl

t Triplet

TBDMS tert-Butyldimethylsilyl

t-Bu t-Butyl

TFA Trifluoroacetic acid

TFAA Trifluoroacetic anhydride

THF Tetrahydrofuran

TLC Think layer chromatography

TMEDA N,N,N’,N’-tetramethylethylenediamine

Ts p-Toluenesulfonyl

UV Ultraviolet

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